Language：English   Publishing type：Research paper (scientific journal)  

Inorganic biomaterials are used in various orthopedic and dental implants. Nevertheless, they cause clinical issues such as loosening of implants and patient morbidity. Therefore, inspired by mussel adhesive proteins, we aimed to design an adhesive and dimer-forming highly active bone morphogenetic protein-2 (BMP-2) using bioorthogonal chemistry, in which recombinant DNA technology was combined with enzymatic modifications, to achieve long-term osseointegration with titanium. The prepared BMP-2 exhibited substantially higher binding activity than wild-type BMP-2, while the adhered BMP-2 was more active than soluble BMP-2. Therefore, the adhesive BMP-2 was immobilized onto titanium wires and screws and implanted into rat bones, and long-term osteogenesis was evaluated. Adhesive BMP-2 promoted the mechanical binding of titanium to bones, enabling efficient bone regeneration and effective stabilization of implants. Thus, such adhesive biosignaling proteins can be used in regenerative medicine.

DOI： 10.1039/d3tb02838k

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.18926/AMO/66664

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Authorship：Last author   Publisher：Springer Science and Business Media LLC  

Abstract

Background

The World Health Organization first declared the coronavirus disease 2019 (COVID-19) pandemic in March 2020 and announced the end of the emergency in May 2023. Additionally, the COVID-19 pandemic significantly impacted individuals globally, including medical students. Although the COVID-19 pandemic increased online education, it restricted clinical training, extracurricular activities, and interprovincial travel. Therefore, this study aimed to examine whether the COVID-19 pandemic influenced the choice of training hospitals and career paths among 3rd- to 6th-year medical students in Japan.

Methods

We developed a questionnaire comprising 21 multiple-choice and 1 open-ended questions, which was administered anonymously via online platforms. The survey targeted Japanese medical students to obtain insights into their preferences for training hospitals and career paths during the COVID-19 pandemic. Participants included 4th- to 6th-year medical students from 51 medical schools in Japan. The survey was conducted through student networks from 8 February 2022 to 20 March 2022.

Results

Overall, 507 medical students participated in the survey, with representation from various academic years as follows: 102 (20.1%), 134 (26.4%), 121 (23.9%), and 150 (29.6%) students from the 3rd, 4th, 5th, and 6th year, respectively. Of these, 338 (66.6%) students reported that the COVID-19 pandemic had influenced their choice of training hospitals. The degree of the influence varied based on the university region and the student year. However, most of the students (473, 93.3%) did not change their course for clinical, basic research, or administrative pathways due to the COVID-19 pandemic. Among the clinically oriented students, 391 (77.2%) did not change their preferred speciality.

Conclusions

The COVID-19 pandemic influenced medical students’ choice of training hospitals. Although many students believed that the pandemic would not change their career choices, our results indicate a potential subconscious trend to avoid internal medicine, which is the speciality most directly involved in treating patients with COVID-19.

DOI： 10.1186/s12909-023-05021-6

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Other Link： https://link.springer.com/article/10.1186/s12909-023-05021-6/fulltext.html

Language：Japanese   Publisher：(一社)日本医学教育学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00050&link_issn=&doc_id=20240119070022&doc_link_id=10.11307%2Fmededjapan.54.6_613&url=https%3A%2F%2Fdoi.org%2F10.11307%2Fmededjapan.54.6_613&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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BACKGROUND: No proven treatment after the development of primary graft dysfunction (PGD) is currently available. Here we established a novel strategy of in vivo lung perfusion (IVLP) for the treatment of PGD. IVLP involves the application of an in vivo isolated perfusion circuit to an implanted lung. This study aimed to explore the effectiveness of IVLP versus conventional post-lung transplant (LTx) extracorporeal membrane oxygenation (ECMO) treatment using an experimental swine LTx PGD model. METHODS: After 1.5-h warm ischemia of the donor lungs, a left LTx was performed. Following the confirmation of PGD development, pigs were divided into three groups (n = 5 each): control (no intervention), ECMO, and IVLP. After 2 h of treatment, a 4-h functional assessment was conducted and samples obtained. RESULTS: Significantly better oxygenation were achieved in the IVLP group (p ≤ 0.001). Recovery was confirmed immediately and maintained during the following 4-h observation. The IVLP group also demonstrated better lung compliance than the control group (p = 0.045). A histological evaluation showed that the lung injury score and terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed significantly fewer injuries and a better result in the wet-to-dry weight ratio in the IVLP group. CONCLUSIONS: A two-hour IVLP is technically feasible and allows for prompt recovery from PGD after LTx. The posttransplant short-duration IVLP strategy can complement or overcome the limitations of the current practice for donor assessment and PGD management.

DOI： 10.1016/j.healun.2023.10.011

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Breast cancer is the most prevalent cancer worldwide, and metastasis is the leading cause of death in cancer patients. Human monocyte chemoattractant protein-1 (MCP-1/CCL2) was isolated from the culture supernatants of not only mitogen-activated peripheral blood mononuclear leukocytes but also malignant glioma cells based on its in vitro chemotactic activity toward human monocytes. MCP-1 was subsequently found to be identical to a previously described tumor cell-derived chemotactic factor thought to be responsible for the accumulation of tumor-associated macrophages (TAMs), and it became a candidate target of clinical intervention; however, the role of TAMs in cancer development was still controversial at the time of the discovery of MCP-1. The in vivo role of MCP-1 in cancer progression was first evaluated by examining human cancer tissues, including breast cancers. Positive correlations between the level of MCP-1 production in tumors and the degree of TAM infiltration and cancer progression were established. The contribution of MCP-1 to the growth of primary tumors and metastasis to the lung, bone, and brain was examined in mouse breast cancer models. The results of these studies strongly suggested that MCP-1 is a promoter of breast cancer metastasis to the lung and brain but not bone. Potential mechanisms of MCP-1 production in the breast cancer microenvironment have also been reported. In the present manuscript, we review studies in which the role of MCP-1 in breast cancer development and progression and the mechanisms of its production were examined and attempt to draw a consensus and discuss the potential use of MCP-1 as a biomarker for diagnosis.

DOI： 10.1038/s41423-023-01013-0

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The downregulation of SPRED2, a negative regulator of the ERK1/2 pathway, was previously detected in human cancers; however, the biological consequence remains unknown. Here, we investigated the effects of SPRED2 loss on hepatocellular carcinoma (HCC) cell function. Human HCC cell lines, expressing various levels of SPRED2 and SPRED2 knockdown, increased ERK1/2 activation. SPRED2-knockout (KO)-HepG2 cells displayed an elongated spindle shape with increased cell migration/invasion and cadherin switching, with features of epithelial-mesenchymal transition (EMT). SPRED2-KO cells demonstrated a higher ability to form spheres and colonies, expressed higher levels of stemness markers and were more resistant to cisplatin. Interestingly, SPRED2-KO cells also expressed higher levels of the stem cell surface markers CD44 and CD90. When CD44+CD90+ and CD44-CD90- populations from WT cells were analyzed, a lower level of SPRED2 and higher levels of stem cell markers were detected in CD44+CD90+ cells. Further, endogenous SPRED2 expression decreased when WT cells were cultured in 3D, but was restored in 2D culture. Finally, the levels of SPRED2 in clinical HCC tissues were significantly lower than those in adjacent non-HCC tissues and were negatively associated with progression-free survival. Thus, the downregulation of SPRED2 in HCC promotes EMT and stemness through the activation of the ERK1/2 pathway, and leads to more malignant phenotypes.

DOI： 10.3390/ijms24054996

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Objectives: The mono-functional monomer 2-hydroxyethyl methacrylate (HEMA) is often added to universal adhesives (UAs) to improve surface wetting and prevent phase separation. Nevertheless, HEMA promotes water sorption and hydrolysis at adhesive interfaces, hereby affecting long-term bonding to dentin. This study investigated if two acrylamide monomers could replace HEMA in an UA formulation applied in etch-and-rinse (2E&R) and self-etch (1SE) bonding mode. Methods: Four experimental UAs were bonded to bur-cut dentin. In addition to 12 wt% 10-MDP, 25 wt% Bis-GMA and 10 wt% TEGDMA as common monomer composition, 20 %wt ethanol and 15 %wt water as solvent, and 3 wt% polymerization-related additives, the four formulations solely differed for either the acrylamide cross-linker monomer ‘FAM-201′ as TEGDMA alternative and HEMA replacement, the hydroxyethyl acrylamide monomer ‘HEAA’ as HEMA alternative, HEMA (‘HEMA+’), or extra TEGDMA in a HEMA-free control (‘HEMA-’), all added in a 15 wt% concentration. The split-tooth study design involved application in 2E&R mode on one tooth half versus 1SE mode on the corresponding half. Micro-tensile bond strength of half of the micro-specimens was measured upon 1-week distilled water storage (‘immediate’ 1w μTBS), with the other half measured after additional 6-month storage (‘aged’ 6 m μTBS). Statistics involved linear mixed-effects (LME) modelling (p < .05). Additionally, interfacial TEM characterization, thin-film (TF) XRD surface analysis, LogP determination, and a cytotoxicity assay were carried out. Results: FAM-201 revealed significantly higher μTBS than HEMA+ at 1w and 6 m when applied both in E&R and SE bonding modes. HEAA's μTBS was significantly lower than that of HEMA+ at 1w when applied in SE mode. TF-XRD and TEM revealed similar chemical and ultrastructural interfacial characterization, including stable 10-MDP_Ca salt nano-layering. FAM-201 was least cytotoxic and presented with an intermediary LogP, while HEAA presented with the highest LogP, indicating high hydrophilicity and water-sorption sensitivity. Significance: The acrylamide co-monomer FAM-201 could replace HEMA in an UA formulation, while HEAA not.

DOI： 10.1016/j.dental.2023.01.003

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DOI： 10.3390/cancers15020468

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Zirconia ceramics have been widely used in dentistry. Herein, we assess the surface morphology, surface texture, and osteoblast response of additively manufactured zirconia and alumina-toughened zirconia (ATZ) in comparison with titanium. The surface roughness, contact angle, and surface microstructure of titanium sandblasted with large-grit alumina and subsequently acid-etched using 18% HCl and 49% H2SO4 (SLA-titanium), uniaxially pressed zirconia (UP zirconia), additively manufactured zirconia (AM zirconia), and additively manufactured ATZ (AM ATZ) were investigated. Moreover, the cell viability, alkaline phosphatase (ALP) activity, and gene expression of type I collagen on these materials were evaluated. The data were statistically analyzed using one-way ANOVA with Tukey's post hoc test. SLA-titanium showed the highest surface roughness and contact angle. The other three materials showed comparable surface roughness and contact angles. Micro- and nanoroughness were observed on the surface of SLA-titanium. UP zirconia and AM zirconia had similar surface morphologies. The cell viability, ALP activity, and gene expression of type I collagen on AM zirconia were comparable to or better than those on SLA-titanium. Our results indicate that AM zirconia is a promising material for zirconia dental implants.

DOI： 10.3390/ma15238685

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(1) Background: Lung ischemia-reperfusion (IR) injury increases the mortality and morbidity of patients undergoing lung transplantation. The objective of this study was to identify the key initiator of lung IR injury and to evaluate pharmacological therapeutic approaches using a functional inhibitor against the identified molecule. (2) Methods: Using a mouse hilar clamp model, the combination of RNA sequencing and histological investigations revealed that neutrophil-derived S100A8/A9 plays a central role in inflammatory reactions during lung IR injury. Mice were assigned to sham and IR groups with or without the injection of anti-S100A8/A9 neutralizing monoclonal antibody (mAb). (3) Results: Anti-S100A8/A9 mAb treatment significantly attenuated plasma S100A8/A9 levels compared with control IgG. As evaluated by oxygenation capacity and neutrophil infiltration, the antibody treatment dramatically ameliorated the IR injury. The gene expression levels of cytokines and chemokines induced by IR injury were significantly reduced by the neutralizing antibody. Furthermore, the antibody treatment significantly reduced TUNEL-positive cells, indicating the presence of apoptotic cells. (4) Conclusions: We identified S100A8/A9 as a novel therapeutic target against lung IR injury.

DOI： 10.3390/bioengineering9110673

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BACKGROUND: Patients with triple-negative breast cancer (TNBC) often have poorer prognosis than those with other subtypes because of its aggressive behaviors. Cancer cells are heterogeneous, and only a few highly metastatic subclones metastasize. Although the majority of subclones may not metastasize, they could contribute by releasing factors that increase the capacity of highly metastatic cells and/or provide a favorable tumor microenvironment (TME). Here, we analyzed the interclonal communication in TNBC which leads to efficient cancer progression, particularly lung metastasis, using the polyclonal murine 4T1 BC model. METHODS: We isolated two 4T1 subclones, LM.4T1 and HM.4T1 cells with a low and a high metastatic potential, respectively, and examined the effects of LM.4T1 cells on the behaviors of HM.4T1 cells using the cell scratch assay, sphere-forming assay, sphere invasion assay, RT-qPCR, and western blotting in vitro. We also examined the contribution of LM.4T1 cells to the lung metastasis of HM.4T1 cells and TME in vivo. To identify a critical factor which may be responsible for the effects by LM.4T1 cells, we analyzed the data obtained from the GEO database. RESULTS: Co-injection of LM.4T1 cells significantly augmented lung metastases by HM.4T1 cells. LM.4T1-derived exosomes promoted the migration and invasion of HM.4T1 cells in vitro, and blocking the secretion of exosome abrogated their effects on HM.4T1 cells. Analyses of data obtained from the GEO database suggested that Wnt7a might be a critical factor responsible for the enhancing effects. In fact, a higher level of Wnt7a was detected in LM.4T1 cells, especially in exosomes, than in HM.4T1 cells, and deletion of Wnt7a in LM.4T1 cells significantly decreased the lung metastasis of HM.4T1 cells. Further, treatment with Wnt7a increased the spheroid formation by HM.4T1 cells via activation of the PI3K/Akt/mTOR signaling pathway. Finally, infiltration of αSMA-positive fibroblasts and angiogenesis was more prominent in tumors of LM.4T1 cells and deletion of Wnt7a in LM.4T1 cells markedly reduced angiogenesis. CONCLUSIONS: We demonstrated, for the first time, that a low metastatic subclone can enhance lung metastasis of highly metastatic subclone via exosomal Wnt7a and propose Wnt7a as a molecular target to treat TNBC patients.

DOI： 10.1186/s13058-022-01557-5

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Although bronchiolitis obliterans syndrome (BOS) is a major cause of death after lung transplantation, an effective drug therapy for BOS has not yet developed. Here, we assessed the effectiveness of a neutralizing anti-S100 calcium binding protein (S100) A8/A9 antibody against BOS. A murine model of heterotopic tracheal transplantation was used. Mice were intraperitoneally administered control IgG or the S100A8/A9 antibody on day 0 and twice per week until they were sacrificed. Tissue sections were used to evaluate the obstruction ratio, epithelium-preservation ratio, α-smooth muscle actin (SMA)-positive myofibroblast infiltration, and luminal cell death. Quantitative reverse transcriptase-polymerase chain reaction analysis was performed to analyze the mRNA-expression levels of collagen, inflammatory cytokines, and chemokines on days 7, 14, and 21. The anti-S100A8/A9 antibody significantly improved the obstruction ratio and epithelium-preservation ratio, with less α-SMA-positive myofibroblast infiltration compared to the control group. Antibody treatment reduced the type-III collagen: type-I collagen gene-expression ratio. The antibody also significantly suppressed the number of dead cells in the graft lumen. The expression levels of tumor growth factor β1 and C-C motif chemokine 2 on day 21, but not those of interleukin-1β, interleukin-6, and tumor necrosis factor α, were significantly suppressed by S100A8/A9 antibody treatment. These findings suggest that S100A8/A9 may be a potential therapeutic target for BOS after lung transplantation.

DOI： 10.1016/j.bbrc.2022.08.087

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Authorship：Last author   Language：Japanese   Publisher：(公社)日本皮膚科学会  

75歳、男性。肛門周囲の紅斑があり、病理組織でPaget細胞を認めた。肛門管に病変がなく皮膚原発のPaget病として手術したが肛門側の断端にPaget細胞あり。免疫染色でCK7(+)、CK20(+)、GCDFP15(-)、CDX2(+)であった。6年後に肛門管の粘液癌が判明し腹会陰式直腸切断術を施行した。肛門腺由来癌は肛門粘膜表面には癌組織がほとんど見られないという特徴や上記の免疫染色結果から当初より肛門腺由来の肛門管癌による二次性Paget病であったと考えた。Paget病変は早期の肛門管癌から生じうるため、免疫染色は肛囲Paget病が皮膚原発か、肛門管癌によるものかの鑑別手段になると考えた。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J01174&link_issn=&doc_id=20220826400006&doc_link_id=10.14924%2Fdermatol.132.2147&url=https%3A%2F%2Fdoi.org%2F10.14924%2Fdermatol.132.2147&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：English  

DOI： 10.1038/s41598-022-11823-3

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Under normal conditions, fasting results in decreased protein disulfide isomerase (PDI) activity and accumulation of unfolded proteins, leading to the subsequent activation of the unfolded protein response (UPR)/autophagy signaling pathway to eliminate damaged mitochondria. Fasting also induces upregulation of thioredoxin-interacting protein (TXNIP) expression and mice deficient of this protein (TXNIP-KO mice) was shown to develop severe hypoglycemia, hyperlipidemia and liver steatosis (LS). In the present study, we aimed to determine the role of TXNIP in fasting-induced LS by using male TXNIP-KO mice that developed LS without severe hypoglycemia. In TXNIP-KO mice, fasting induced severe microvesicular LS. Examinations by transmission electron microscopy revealed mitochondria with smaller size and deformities and the presence of few autophagosomes. The expression of β-oxidation-associated genes remained at the same level and the level of LC3-II was low. PDI activity level stayed at the original level and the levels of p-IRE1 and X-box binding protein 1 spliced form (sXBP1) were lower. Interestingly, treatment of TXNIP-KO mice with bacitracin, a PDI inhibitor, restored the level of LC3-II after fasting. These results suggest that TXNIP regulates PDI activity and subsequent activation of the UPR/autophagy pathway and plays a protective role in fasting-induced LS.

DOI： 10.1038/s41598-022-08791-z

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BACKGROUND: Anti-programmed death 1/programmed death ligand 1 (PD1/PD-L1) antibodies have been successfully used as treatment agents for several solid tumors; however, it is difficult to predict their effectiveness. We evaluated whether biopsy specimens could predict the positive status of PD-L1 in surgically resected tissue. METHODS: Among 91 patients who underwent tissue sampling with endoscopic or liver biopsy before surgery for biliary tract neoplasms in an academic center, 45 (49%) patients were selected for retrospective analysis because the quality and quantity of their biopsy specimens were adequate for histologic evaluation. We performed immunohistochemical staining to investigate the PD-L1 expression in both resected and biopsy specimens. The percentage of the positively stained cells was calculated for subsequent use in the correlation investigation. RESULTS: The biopsy methods were endoscopic retrograde cholangiopancreatography (ERCP) in 28 cases, percutaneous liver biopsy in 10 cases, and endoscopic ultrasound fine-needle aspiration in 7 cases. Among the 45 patients, when patients with > 10% positive tumor cells in surgically resected tissues were regarded as truly positive PD-L1, the positive and negative concordance rates between surgically resected tissues and biopsy samples were 56% (5/9) and 100% (36/36), respectively. With regard to the use of preoperative biopsy as a diagnostic tool, all (5/5) PD-L1-positive patients had a positive resected specimen. The accuracy of each biopsy method was as follows: ERCP, 89% (25/28); fine-needle aspiration, 86% (6/7); and liver biopsy, 100% (10/10). CONCLUSIONS: Biopsy samples could be a surrogate material for the assessment of the PD-L1 expression with substantial positive and high negative concordance rates.

DOI： 10.1007/s11605-021-05197-6

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Plant biomass could be a viable alternative renewable resource, but the moisture content must be reduced to use it as fuel. Mechanical compression alone is generally insufficient for dehydration, necessitating the addition of thermal drying. This study develops a unique mechanical rolling compression method with high dehydration ability. The squeezed liquid was analyzed using 1H nuclear magnetic resonance (1H NMR), UV–Vis, and FT-IR indicating much water-soluble lignin. Cedar board, woody biomass, compressed more effectively than cedar chips, implying that mechanical rolling compression along vessels such as straw was important. Alpinia zerumbet, herbaceous biomass, was compressed in the same way, and the squeezed liquid contained water-soluble lignin. Pellets made from plant residues were evaluated by combustion test. The squeezed liquid with water-soluble liquid revealed a basic antiviral effect for influenza and the porcine epidemic diarrhea virus. Our developed, novel, rolling plant compression method has the potential to alter fossil fuels.

DOI： 10.1007/s10163-022-01531-5

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Language：Japanese   Publisher：尾道市立市民病院  

2016年12月より細胞診標本作製後の残検体を用いた遺伝子変異解析や発現タンパクの検出を目的とした簡易セルブロックの作製を開始した。同時に、細胞診とセルブロックとの併用による診断精度の向上にも取り組んだ。今回、2021年3月までにセルブロックを作製した68例について有用性を検討した。その結果、細胞診残検体によるセルブロックを用いて免疫染色を追加でき、良悪性の鑑別に加えて組織型の決定も可能となった症例があった。さらに組織検体を採取できない症例でもコンパニオン診断を実施できるようになり、セルブロックの有用性が認められた。(著者抄録)

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The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) is shown to promote the progression of breast cancer. We previously identified cancer cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential regulator of MCP-1 production in the murine 4T1 breast cancer, but it played a minimum role in overall MCP-1 production. Here, we evaluated the crosstalk between 4T1 cells and fibroblasts. When fibroblasts were co-cultured with 4T1 cells or stimulated with the culture supernatants of 4T1 cells (4T1-sup), MCP-1 production by fibroblasts markedly increased. 4T1 cells expressed mRNA for platelet-derived growth factor (PDGF)-a, b and c, and the PDGF receptor inhibitor crenolanib almost completely inhibited 4T1-sup-induced MCP-1 production by fibroblasts. However, PDGF receptor antagonists failed to reduce MCP-1 production in tumor-bearing mice. Histologically, 4T1 tumors contained a small number of αSMA-positive fibroblasts, and Mcp-1 mRNA was mainly associated with macrophages, especially those surrounding necrotic lesions on day 14, by in situ hybridization. Thus, although cancer cells have the capacity to crosstalk with fibroblasts via PDGFs, this crosstalk does not play a major role in MCP-1 production or cancer progression in this model. Unraveling complex crosstalk between cancer cells and stromal cells will help us identify new targets to help treat breast cancer patients.

DOI： 10.3390/cimb43030122

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During ischemia reperfusion (IR) injury, high mobility group box 1 (HMGB1), a chromatin binding protein, is released from necrotic cells and triggers inflammatory responses. We assessed the therapeutic effect of a neutralizing anti-HMGB1 monoclonal antibody (mAb) on lung IR injury. A murine hilar clamp model of IR was used, where mice were divided into sham and IR groups with intravenous administration of anti-HMGB 1 mAb or control mAb. We analyzed the effect of anti-HMGB1 mAb against IR injury by assessing lung oxygenation, lung injury score, neutrophil infiltration, expression of proinflammatory cytokines and chemokines, levels of mitogen-activated protein kinase (MAPK) signaling, and measurement of apoptotic cells. Anti-HMGB1 mAb significantly decreased the plasma level of HMGB1 elevated by IR. The severity of IR injury represented by oxygenation capacity, lung injury score, and neutrophil infiltration was significantly improved by anti-HMGB1 mAb treatment. The expression of proinflammatory factors, including IL-1β, IL-6, IL-12, TNF-α, CXCL-1, and CXCL-2, and phosphorylation of p38 MAPK were both significantly reduced by anti-HMGB1 mAb treatment. Furthermore, anti-HMGB1 mAb treatment suppressed apoptosis, as determined through TUNEL assays. Overall, anti-HMGB1 mAb ameliorated lung IR injury by reducing inflammatory responses and apoptosis. Our findings indicate that anti-HMGB1 mAb has potential for use as a therapeutic to improve IR injury symptoms during lung transplantation.

DOI： 10.1016/j.bbrc.2021.08.015

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BACKGROUNDS: Epithelial mesenchymal transition (EMT) is a critical process involved in the invasion and metastasis of cancer, including lung cancer (LC). Transforming growth factor (TGF)-β is one of factors capable of inducing EMT. Polyinosinic-polycytidylic acid (polyI:C), a synthetic agonist for toll-like receptor (TLR) 3, can enhance immune responses and has been used as an adjuvant for cancer vaccines; however, it remains unclear whether it influences other process, such as EMT. In the present study, we examined the effects of polyI:C on TGF-β-treated A549 human LC cells. METHODS AND RESULTS: By in vitro cell proliferation assay, polyI:C showed no effect on the growth of A549 cells treated with TGF-β1 at the concentration range up to 10 μg/ml; however, it markedly suppressed the motility in a cell scratch and a cell invasion assay. By Western blotting, polyI:C dramatically decreased TGF-β1-induced Ak strain transforming (Akt) phosphorylation and increased phosphatase and tensin homologue (PTEN) expression without affecting the Son of mothers against decapentaplegic (Smad) 3 phosphorylation or the expression level of E-cadherin, N-cadherin or Snail, indicating that polyI:C suppressed cell motility independently of the 'cadherin switching'. The Akt inhibitor perifosine inhibited TGF-β1-induced cell invasion, and the PTEN-specific inhibitor VO-OHpic appeared to reverse the inhibitory effect of polyI:C. CONCLUSION: PolyI:C has a novel function to suppress the motility of LC cells undergoing EMT by targeting the phosphatidylinositol 3-kinase/Akt pathway partly via PTEN and may prevent or reduce the metastasis of LC cells.

DOI： 10.1007/s11033-021-06625-1

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Cancer-specific metabolic alterations hyperactivate the kinase activity of the mammalian/mechanistic target of rapamycin (mTOR) for overcoming stressful environments. Rapalogs, which allosterically inhibit mTOR complex 1 (mTORC1), have been approved as anticancer agents. However, the immunosuppressive side effect of these compounds results in the promotion of tumor metastasis, thereby limiting their therapeutic efficacy. We first report a nonrapalog inhibitor, WRX606, identified by a hybrid strategy of in silico and in cell selections. Our studies showed that WRX606 formed a ternary complex with FK506-binding protein-12 (FKBP12) and FKBP-rapamycin-binding (FRB) domain of mTOR, resulting in the allosteric inhibition of mTORC1. WRX606 inhibited the phosphorylation of not only the ribosomal protein S6 kinase 1 (S6K1) but also eIF4E-binding protein-1 (4E-BP1). Hence, WRX606 efficiently suppressed tumor growth in mice without promotion of metastasis. These results suggest that WRX606 is a potent lead compound for developing anticancer drugs discovered by in silico and in cell methods.

DOI： 10.1021/acs.jmedchem.1c00536

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Esophageal cancer is a disease showing poor prognosis. Although combination chemotherapy using cisplatin and 5-fluorouracil is standard for unresectable esophageal cancer, the response rate is 35%. Cancer stem cells (CSCs) and inflammation are reportedly responsible for the poor prognosis of esophageal cancer. However, comprehensive analyses have not been conducted and proposals for progress remain lacking. Iron is known to be a key factor in the stemness of CSCs. This study focused on the therapeutic potential of iron control using iron chelators for CSCs in esophageal cancer. Among 134 immunohistochemically analyzed cases, Nanog expression was high in 98 cases and low in 36 cases. High Nanog expression correlated with low overall and disease-free survivals. The iron chelators deferasirox (DFX) and SP10 suppressed the proliferation and expression of stemness markers in TE8 and OE33 cells. DFX and SP10 did not induce compensatory interleukin (IL)-6 secretion, although cisplatin did result in high induction. Moreover, BBI608 and SSZ, as other CSC-targeting drugs, could not suppress the expression of stemness markers. Together, Nanog expression appears related to poor prognosis in esophageal cancer patients, and inhibition of stemness and compensatory IL-6 secretion by iron chelators may offer a novel therapeutic strategy for esophageal cancer.

DOI： 10.1002/ijc.33544

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The utility of gastric biopsy for diagnosing immunoglobulin (Ig)G4-related gastrointestinal disease (IgG4-GID) remains unclear. Bottom-heavy plasmacytosis (BHP) is a distinct feature of IgG4-GID. To clarify the feasibility of using gastric biopsies to diagnose BHP in IgG4-GID, we analyzed the histological features and immunostaining of gastric biopsy specimens from 31 known IgG4-related disease (IgG4-RD) patients and we assessed the presence of BHP in 1696 consecutive routine gastric biopsies. Cases with both >10 IgG4-positive plasma cells per high-power field and an IgG4/IgG-positive ratio >40% were defined as IgG4-high. Ten of the 31 IgG4-RD patients were concluded to have IgG4-GID, in which IgG4-positive plasma cells were notably detected at the deeper part of the mucosa. Six cases displayed BHP whereas the remaining four cases showed transmural infiltration with concomitant Helicobacter pylori-associated gastritis. In addition to BHP, we identified two unique histologic features for IgG4-GID: plasmacytic aggregation in the muscularis mucosae and permeative plasmacytic infiltration between fundic glands in the non-atrophic mucosa. Six of the routine cases (0.35%) displayed BHP, including a case with IgG4-RD. IgG4-GID can be suspected by the presence of gastric biopsy specimens with characteristic histological features. Such cases are recommended to undergo further examinations to determine whether IgG4-RD is present.

DOI： 10.1111/pin.13059

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Aberrant activation of the Ras/Raf/ERK (extracellular-signal-regulated kinase)-MAPK (mitogen-activated protein kinase) pathway is involved in the progression of cancer, including urothelial carcinoma; but the negative regulation remains unclear. In the present study, we investigated pathological expression of Spred2 (Sprouty-related EVH1 domain-containing protein 2), a negative regulator of the Ras/Raf/ERK-MAPK pathway, and the relation to ERK activation and Ki67 index in various categories of 275 urothelial tumors obtained from clinical patients. In situ hybridization demonstrated that Spred2 mRNA was highly expressed in high-grade non-invasive papillary urothelial carcinoma (HGPUC), and the expression was decreased in carcinoma in situ (CIS) and infiltrating urothelial carcinoma (IUC). Immunohistochemically, membranous Spred2 expression, important to interact with Ras/Raf, was preferentially found in HGPUC. Interestingly, membranous Spred2 expression was decreased in CIS and IUC relative to HGPUC, while ERK activation and the expression of the cell proliferation marker Ki67 index were increased. HGPUC with membranous Spred2 expression correlated significantly with lower levels of ERK activation and Ki67 index as compared to those with negative Spred2 expression. Thus, our pathological findings suggest that Spred2 counters cancer progression in non-invasive papillary carcinoma possibly through inhibiting the Ras/Raf/ERK-MAPK pathway, but this regulatory mechanism is lost in cancers with high malignancy. Spred2 appears to be a key regulator in the progression of non-invasive bladder carcinoma.

DOI： 10.1371/journal.pone.0254289

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

The mitogen-activated protein kinase (MAPK) pathways are involved in many cellular processes, including the development of fibrosis. Here, we examined the role of Sprouty-related EVH-1-domain-containing protein (Spred) 2, a negative regulator of the MAPK-ERK pathway, in the development of bleomycin (BLM)-induced pulmonary fibrosis (PF). Compared to WT mice, Spred2-/- mice developed milder PF with increased proliferation of bronchial epithelial cells. Spred2-/- lung epithelial cells or MLE-12 cells treated with spred2 siRNA proliferated faster than control cells in vitro. Spred2-/- and WT macrophages produced similar levels of TNFα and MCP-1 in response to BLM or lipopolysaccharide and myeloid cell-specific deletion of Spred2 in mice had no effect. Spred2-/- fibroblasts proliferated faster and produced similar levels of MCP-1 compared to WT fibroblasts. Spred2 mRNA was almost exclusively detected in bronchial epithelial cells of naïve WT mice and it accumulated in approximately 50% of cells with a characteristic of Clara cells, 14 days after BLM treatment. These results suggest that Spred2 is involved in the regulation of tissue repair after BLM-induced lung injury and increased proliferation of lung bronchial cells in Spred2-/- mice may contribute to faster tissue repair. Thus, Spred2 may present a new therapeutic target for the treatment of PF.

DOI： 10.1038/s41598-020-73752-3

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Language：Japanese   Publisher：(一社)日本病理学会  

胎児期に一過性骨髄異常増殖症(transient abnormal myelopoiesis:TAM)を発症し、生後4日で死亡したダウン症候群の新生児の1剖検例を経験した。母体は20代の経産婦で、妊娠31週5日に胎児機能不全を認め緊急帝王切開となった。患児は新生児仮死の状態であった。出生直後の末梢血は白血球数が異常高値で、塗抹標本で多数の巨核球系の芽球を認めた。染色体検査で21トリソミーと判明したため、TAMと診断した。組織学的に、胎盤では絨毛の血管が消失した領域が認められ、fetal vascular malperfusion(FVM)と考えた。腫瘍細胞が絨毛内の血管内腔に充満し、血栓形成を伴っている像を認め、TAMがFVMの一因であることが推測された。(著者抄録)

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Blood vessel invasion (BVI) is a prognostic indicator in various cancers. Elastic stain, which highlights blood vessel walls, is commonly used to detect BVI. In the breast, however, its diagnostic usefulness is limited because it also highlights some intraductal carcinoma components, which often mimic BVI. In this study, we aimed to improve BVI detection in breast cancer and developed a double staining: Victoria blue for elastin and immunohistochemistry for collagen IV. Collagen IV fibers were retained along the basement membranes of intraductal carcinoma components, whereas they were rearranged or lost in BVI. From these observations, we defined BVI as the presence of tumor cells inside an elastic ring with a rearrangement or loss of collagen IV fibers. Using these criteria, we found BVI in 148 cases (49%) among 304 cases of primary operable invasive breast carcinoma, and the presence of BVI correlated significantly with poor prognosis. By contrast, we detected BVI in 94 cases (31%) or 14 cases (5%) by elastic van Gieson or CD31 immunostaining among the same cases, respectively, with no statistically significant association with prognosis. Thus, elastin and collagen IV double staining facilitates the detection of BVI in breast cancer and is useful to predict prognosis.

DOI： 10.1111/pin.12971

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Transcription factor ERG (erythroblast transformation-specific (ETS)-related gene) is essential in endothelial differentiation and angiogenesis, in which microRNA (miR)-200b-3p targeting site is expected by miRNA target prediction database. miR-200b is known decreased in hepatocellular carcinoma (HCC), however, the functional relation between ERG and miR-200b-3p, originating from pre-miR-200b, in HCC angiogenesis remains unclear. We investigated whether hepatocyte-derived miR-200b-3p governs angiogenesis in HCC by targeting endothelial ERG. Levels of miR-200b-3p in HCC tissues were significantly lower than those in adjacent non-HCC tissues. Poorly differentiated HCC cell line expressed lower level of miR-200b-3p compared to well-differentiated HCC cell lines. The numbers of ERG-positive endothelial cells were higher in HCC tissues than in adjacent non-HCC tissues. There was a negative correlation between the number of ERG-positive cells and miR-200b-3p expression in HCC tissues. Culture supernatants of HCC cell lines with miR-200b-3p-overexpression reduced cell migration, proliferation and tube forming capacity in endothelial cells relative to the control, while those with miR-200b-3p-inhibition augmented the responses. Exosomes isolated from HCC culture supernatants with miR-200b-3p overexpression suppressed endothelial ERG expression. These results suggest that exosomal miR-200b-3p from hepatocytes suppresses endothelial ERG expression, and decreased miR-200b-3p in cancer cells promotes angiogenesis in HCC tissues by enhancing endothelial ERG expression.

DOI： 10.1038/s41598-020-67425-4

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Several studies have shown the clinical success of hydraulic calcium-silicate cements (hCSCs) for direct and indirect pulp capping and root repair. However, hCSCs have various drawbacks, including long setting time, poor mechanical properties, low bond strength to dentin, and relatively poor handling characteristics. To overcome these limitations, a light-curable, resin-based hCSC (Theracal LC, Bisco) was commercially introduced; however, it did not exhibit much improvement in bond strength. We developed a light-curable self-adhesive pulp-capping material that contains the novel acrylamide monomer N,N'-{[(2-acrylamido-2-[(3-acrylamidopropoxy)methyl]propane-1,3-diyl)bis(oxy)]bis(propane-1,3-diyl)}diacrylamide (FAM-401) and the functional monomer 4-methacryloxyethyl trimellitate anhydride (4-MET). Two experimental resin-based hCSCs containing different calcium sources (portlandite: Exp_Pl; tricalcium silicate cement: Exp_TCS) were prepared, and the commercial hCSCs Theracal LC and resin-free hCSC Biodentine served as controls. The performance of each cement was evaluated based on parameters relevant for vital pulp therapy, such as curing degree on a wet surface, mechanical strength, as determined using a three-point bending test, shear bond strength to dentin, cytotoxicity, as determined using an MTT assay, and the amount of calcium released, as determined using inductively coupled plasma atomic emission spectrometry. Both experimental cements cured on wet surfaces and showed relatively low cytotoxicity. Furthermore, their flexural and shear bond strength to dentin were significantly higher than those of the commercial references. High calcium release was observed for both Exp_Pl and Biodentine. Thus, Exp_Pl as a new self-adhesive pulp-capping agent performed better than the commercial resin-based pulp-capping agent in terms of mechanical strength, bond strength, and calcium release.

DOI： 10.1039/d0tb00079e

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Language：Japanese   Publisher：(一社)日本医学教育学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00050&link_issn=&doc_id=20200708060031&doc_link_id=%2Fed9jmded%2F2020%2F005103%2F033%2F0279-0281%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fed9jmded%2F2020%2F005103%2F033%2F0279-0281%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Juvenile granulosa cell tumors (JGCTs) are rare ovarian tumors with overall good prognoses. They differ from adult granulosa cell tumors (AGCTs), which are well known for late recurrence. Most JGCTs (～97%) occur in individuals <30 years old. We report a recurrent JGCT in a 40-year-old woman 5 years after initial presentation. The histological appearance and lack of 402C>G missense point mutation of FOXL2 gene (characteristic of AGCT but absent in JGCT) allowed differentiation from AGCT. This is the first comprehensive report of JGCT with late recurrence. Although rare, late recurrence of JGCT can occur; long-term surveillance is suggested.

DOI： 10.18926/AMO/58275

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Iron is a trace but vital element in the human body and is necessary for a multitude of crucial processes in life. However, iron overload is known to induce carcinogenesis via oxidative stress. Cancer cells require large amounts of iron for their rapid division and cell growth. Iron was recently found to play a role in cancer stem cells (CSCs); it maintains stemness during development. Iron also plays an important role in stemness by moderating reactive oxygen species. Thus, iron metabolism in CSCs is a promising therapeutic target. In this review, we summarize the roles of iron in cancer cells and CSCs. We also summarize anti-cancer therapeutic studies with iron chelators and describe our expectation of a new therapeutic strategy for CSCs on the basis of our findings.

DOI： 10.18926/AMO/57946

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In 2016, Gunma University Hospital's Medical Accident Investigation Committee released a report reiterating the necessity of medical education and the need for surgeons to master non-technical skills. We designed a 17-h training course for surgical instructors, designed to teach participants how to sufficiently educate surgeon trainees and encourage their professional identity formation. A post-training survey showed that participants improved their awareness, and their behavioral changes led to favorable team performances. We then began offering a 3-h workshop focusing on the participants' experiences. We propose that the training course using participant narratives is required and effective to establish surgeons' self-reflection and professional identity as surgeons.

DOI： 10.18926/AMO/57956

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We previously reported that 4T1 murine breast cancer cells produce GM-CSF that up-regulates macrophage expression of several cancer promoting genes, including Mcp-1/Ccl2, Ccl17 and Rankl, suggesting a critical role of cancer cell-derived GM-CSF in cancer progression. Here, we attempted to define whether 4T1 cell-derived GM-CSF contributes to the expression of these genes by 4T1tumors, and their subsequent progression. Intraperitoneal injection of anti-GM-CSF neutralizing antibody did not decrease the expression of Mcp-1, Ccl17 or Rankl mRNA by 4T1 tumors. To further examine the role of cancer cell-derived GM-CSF, we generated GM-CSF-deficient 4T1 cells by using the Crisper-Cas9 system. As previously demonstrated, 4T1 cells are a mixture of cells and cloning of cells by itself significantly reduced tumor growth and lung metastasis. By contrast, GM-CSF-deficiency did not affect tumor growth, lung metastasis or the expression of these chemokine and cytokine genes in tumor tissues. By in-situ hybridization, the expression of Mcp-1 mRNA was detected in both F4/80-expressing and non-expressing cells in tumors of GM-CSF-deficient cells. These results indicate that cancer cell-derived GM-CSF is dispensable for the tuning of the 4T1 tumor microenvironment and the production of MCP-1, CCL17 or RANKL in the 4T1 tumor microenvironment is likely regulated by redundant mechanisms.

DOI： 10.3390/ijms20246342

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Spinal cord injury (SCI) results in neural tissue loss and so far untreatable functional impairment. In addition, at the initial injury site, inflammation induces secondary damage, and glial scar formation occurs to limit inflammation-mediated tissue damage. Consequently, it obstructs neural regeneration. Many studies have been conducted in the field of SCI; however, no satisfactory treatment has been established to date. Hepatocyte growth factor (HGF) is one of the neurotrophic growth factors and has been listed as a candidate medicine for SCI treatment. The highlighted effects of HGF on neural regeneration are associated with its anti-inflammatory and anti-fibrotic activities. Moreover, HGF exerts positive effects on transplanted stem cell differentiation into neurons. This paper reviews the mechanisms underlying the therapeutic effects of HGF in SCI recovery, and introduces recent advances in the clinical applications of HGF therapy.

DOI： 10.3390/ijms20236078

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Ischemia-reperfusion injury (IRI) after lung transplantation mainly contributes to the development of primary graft dysfunction. The Sprouty-related EVH1-domain-containing (SPRED) protein family inhibits the mitogen activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway. Our study was aimed at examining the role of SPRED2 in IRI in mice that received orthotopic lung transplantation. Syngeneic mouse lung transplantation was performed in wild-type C57BL/6 J (WT) mice and Spred2 knockout (Spred2-/-) mice on the C57BL/6 J background from the WT donor. Four hours after reperfusion, blood gas analysis was performed, and lung grafts were sacrificed and analyzed. By using arterial oxygen tension measurements and histological evaluation using Lung Injury Score, we revealed more severe IRI in the grafts transplanted to Spred2-/- recipients, which manifested as exacerbated airway epithelial cell damage, interstitial edema with hemorrhage and neutrophil infiltration. Intragraft ERK1/2 activation and expression levels of proinflammatory cytokines and chemokines in Spred2-/- recipients were higher than those in WT recipients. SPRED2 plays an important role in protecting the lungs from IRI in lung transplantation recipients. We suggest that focused treatments suppressing the activity of the MAPK/ERK pathway in transplantation recipients could be the potential therapeutic option for the prevention of lung IRI.

DOI： 10.1016/j.trim.2019.101242

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Long-term anti-bacterial effect is a desired ability of any dental material in combating tooth caries as one of the most common and widespread persistent diseases today. Among several cationic quaternary ammonium compounds with antiseptic properties, cetylpyridinium chloride (CPC) is often used in mouthrinses and toothpastes. In this study, we incorporated CPC in a soft phyllosilicate mineral (clay), referred to as montmorillonite (Mont), to enable gradual CPC release with rechargeability. Besides measuring CPC release and recharge, we examined the anti-bacterial effect, cytotoxicity and bonding effectiveness of five experimental adhesive formulations, prepared by adding 1 and 3 wt% CPC_Mont, 3 wt% Mont (without CPC), and 1 and 3 wt% CPC (without Mont) to the commercial adhesive Clearfil S3 Bond ND Quick ('C-S3B'; Kuraray Noritake). Strong inhibition of Streptococcus mutans biofilm formation by CPC_Mont adhesives was confirmed by optical density and SEM. CPC release from CPC_Mont adhesives was higher and lasted longer than from CPC adhesives, while CPC_Mont adhesives could also be recharged with CPC upon immersion in 2 wt% CPC. In conclusion, CPC_Mont technology rendered adhesives anti-bacterial properties with recharge ability, this without reducing its bonding potential, neither increasing its cytotoxicity. STATEMENT OF SIGNIFICANCE: Dental caries is one of the most prevalent chronic diseases in the population worldwide and is the major cause of tooth loss. In this study, we developed cetylpyridinium chloride (CPC) loaded montmorillonite (CPC-Mont) with a long-term antibacterial efficacy to prevent caries. CPC is an antibacterial agent approved by FDA, used as an OTC drug and contained in oral hygiene aids. CPC-Mont was incorporated in a dental adhesive to gradually release CPC. CPC_Mont technology rendered adhesives anti-bacterial properties with rechargeability, this without reducing its bonding potential, neither increasing its cytotoxicity.

DOI： 10.1016/j.actbio.2019.09.045

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BACKGROUND: Recently, therapeutic antibodies against programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) have shown promising clinical results for several solid tumors, including pancreatic cancer. In this study, we evaluated the relationship between the PD-L1 expression of surgical resected and fine-needle aspiration (FNA) specimens for patients with pancreatic cancer. METHODS: Of 121 patients who underwent endoscopic ultrasound-guided (EUS)-FNA before surgery for pancreatic cancer in an academic center, the 94 (78%) with adequate FNA specimens for a histological evaluation were retrospectively analyzed. All the patients had undergone upfront surgery without any chemotherapy or radiotherapy. We performed immunohistochemistry (IHC) staining to investigate the PD-L1 expression in both resected and FNA specimens. The positive-stained cells were counted, and their percentage was used for the investigation. RESULTS: Of the 94 patients, 16 (17%) and 11 (10%) were defined as positive on resected cancer specimens using cutoff points of 5% and 10% positively stained cancer cell counts, respectively. The concordance rates for the positive frequency of PD-L1 expression between resected and FNA specimens were 44% (7/16) and 55% (6/11) when the positivity was set to ≥ 5% and ≥ 10%, respectively. The concordance rates for the negative frequency of PD-L1 expression between two specimens were 97% (76/78) and 99% (82/83) when the positivity was set to ≥ 5% and ≥ 10%, respectively. CONCLUSIONS: Approximately, half of the patients with PD-L1 expression positive and almost all the patients with PD-L1 expression negative could be diagnosed on FNA specimens.

DOI： 10.1007/s00535-019-01586-6

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OBJECTIVE: In lung transplantation (LTx) from donation after cardiac death (DCD), the donor lungs are inevitably exposed to warm ischemic time (WIT) between the cardiac arrest and the initiation of cold preservation. We conducted this study to examine the effect of prolonged WIT on lung allograft rejection in a murine model of LTx from DCD. METHODS: Allogeneic BALB/c → B6 LTx from DCD was performed with a WIT of 15 min (WIT15 group, n = 5) or 60 min (WIT60 group, n = 5). Recipients were immunosuppressed by perioperative costimulatory blockade. The lung allografts were analyzed by histology and flow cytometry on day 7 after the LTx. RESULTS: Histologically, the rejection grade in the WIT60 group was significantly higher than that in the WIT15 group (3.4 ± 0.4 vs. 2.2 ± 0.2, P = 0.0278). Moreover, the intragraft CD8+ to CD4+ T cell ratio in the WIT60 group was significantly higher than that in the WIT15 group (2.3 ± 0.12 vs. 1.2 ± 0.11, P < 0.0001). CONCLUSIONS: Prolonged WIT could exacerbate the severity of lung allograft rejection after LTx from DCD. Minimization of the WIT could improve the outcomes after LTx from DCD.

DOI： 10.1007/s11748-019-01181-9

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PURPOSE: Suppressor of cytokine signaling-3 (SOCS3) is a negative feedback inhibitor of cytokine signaling with T-cell-mediated immunosuppressive effects on obliterative bronchiolitis (OB). In this study, we aimed to investigate the impact of T-cell-specific overexpression of SOCS3 using a murine heterotopic tracheal transplantation (HTT) model. METHODS: Tracheal allografts from BALB/c mice were subcutaneously transplanted into wild-type C57BL/6J (B6; WT) mice and SOCS3 transgenic B6 (SOCS3TG) mice. Tracheal allografts were analyzed by immunohistochemistry and quantitative polymerase chain reaction assays at days 7 and 21. RESULTS: At day 21, allografts in SOCS3TG mice showed significant amelioration of airway obstruction and epithelial loss compared with allografts in WT mice. The intragraft expression of IFN-γ and CXCL10 was suppressed, while that of IL-4 was enhanced in SOCS3TG mice at day 7. The T-bet levels were lower in SOCS3TG allografts than in WT allografts at day 7. CONCLUSION: We revealed that the overexpression of SOCS3 in T cells effectively ameliorates OB development in a murine HTT model by inhibiting the Th1 phenotype in the early phase. Our results suggest that the regulation of the T-cell response, through the modulation of SOCS expression, has potential as a new therapeutic strategy for chronic lung allograft dysfunction.

DOI： 10.1007/s00595-018-1753-5

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Human pandemic H1N1 2009 influenza virus causes significant morbidity and mortality with severe acute lung injury due to the excessive inflammatory reaction, even with neuraminidase inhibitor use. The anti-inflammatory effect of anti-high-mobility group box-1 (HMGB1) monoclonal antibody (mAb) against influenza pneumonia has been reported. In this study, we evaluated the combined effect of anti-HMGB1 mAb and peramivir against pneumonia induced by influenza A (H1N1) virus in mice. Nine-week-old male C57BL/6 mice were inoculated with H1N1 and treated with intramuscularly administered peramivir at 2 and 3 days post-infection (dpi). The anti-HMGB1 mAb or a control mAb was administered at 2, 3, and 4 dpi. Survival rates were assessed, and lung lavage and pathological analyses were conducted at 5 and 7 dpi. The combination of peramivir with the anti-HMGB1 mAb significantly improved survival rate whereas the anti-HMGB1 mAb alone did not affect virus proliferation in the lungs. This combination therapy also significantly ameliorated histopathological changes, neutrophil infiltration, and macrophage aggregation by inhibiting HMGB1, inflammatory cytokines, and oxidative stress. Fluorescence immunostaining showed that the anti-HMGB1 mAb inhibited HMGB1 translocation from type I alveolar epithelial cells. In summary, combining anti-HMGB1 with conventional anti-influenza therapy might be useful against severe influenza virus infection.

DOI： 10.1002/jmv.25330

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Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.

DOI： 10.3390/cancers11020177

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Influenza-associated encephalopathy (IAE) is a serious complication that can follow influenza virus infection. Once a cytokine storm is induced during influenza virus infection, tight junction protein disruption occurs, which consequently leads to blood-brain barrier (BBB) breakdown. However, the details of IAE pathogenesis are not well understood. Here, we established a murine IAE model by administration of lipopolysaccharide following influenza virus infection. Brains from IAE model mice had significantly higher expression of type I interferons and inflammatory cytokines. In addition, the expression of Caveolin-1, one of the key proteins that correlate with protection of the BBB, was significantly lower in brains from the IAE group compared with the control group. We also found that, among 84 different histone modification enzymes, only SET domain bifurcated 2 (Setdb2), one of the histone methyltransferases that methylates the lysine 9 of histone H3, showed significantly higher expression in the IAE group compared with the control group. Furthermore, chromatin immunoprecipitation revealed that methylation of histone H3 lysine 9 was correlated with repression of the Caveolin-1 promoter region. These studies identify Caveolin-1 as a key regulator of BBB permeability in IAE and reveal that it acts through histone modification induced by Setdb2.

DOI： 10.1038/s41598-018-36489-8

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Chronic low-grade inflammation in visceral adipose tissues triggers the development of obesity-related insulin resistance, leading to the metabolic syndrome, a serious health condition with higher risk of cardiovascular disease, diabetes, and stroke. In the present study, we investigated whether Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, plays a role in the development of high fat diet (HFD)-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance. Spred2 knockout (KO) mice, fed with HFD, exhibited an augmented body weight gain, which was associated with enhanced adipocyte hypertrophy in mesenteric white adipose tissue (mWAT) and deteriorated dyslipidemia, compared with wild-type (WT) controls. The number of infiltrating macrophages with a M1 phenotype, and the crown-like structures, composed of macrophages surrounding dead or dying adipocytes, were more abundant in Spred2 KO-mWAT compared to in WT-mWAT. Exacerbated adipose tissue inflammation in Spred2 KO mice led to aggravated insulin resistance and fatty liver disease. To analyze the mechanism(s) that caused adipose tissue inflammation, cytokine response in mWAT was investigated. Stromal vascular fraction that contained macrophages from Spred2 KO-mWAT showed elevated levels of tumor necrosis factor α (TNFα) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared with those from WT-mWAT. Upon stimulation with palmitate acid (PA), bone marrow-derived macrophages (BMDMs) derived from Spred2 KO mice secreted higher levels of TNFα and MCP-1 than those from WT mice with enhanced ERK activation. U0126, a MEK inhibitor, reduced the PA-induced cytokine response. Taken together, these results suggested that Spred2, in macrophages, negatively regulates high fat diet-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance by inhibiting the ERK/MAPK pathway. Thus, Spred2 represents a potential therapeutic tool for the prevention of insulin resistance and resultant metabolic syndrome.

DOI： 10.3389/fimmu.2019.00017

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PURPOSE: Inflammatory changes during lung ischemia-reperfusion injury (IRI) are related to the activation of the extracellular signal-regulated kinase (ERK)1/2 signaling pathway. Sprouty-related EVH1 (enabled/vasodilator-stimulated phosphoprotein homology 1)-domain-containing proteins (SPREDs) are known inhibitors of ERK1/2 signaling. The role of SPRED2 in lung IRI was examined in a left hilar clamp mouse model. METHODS: C57BL/6 wild-type (WT) and Spred2-/- mice were used in the left hilar clamp model. Experimental groups underwent 30 min of left hilar clamping followed by 1 h of reperfusion. U0126, an ERK1/2 inhibitor, was administered to Spred2-/- mice with reperfused lungs. RESULTS: The partial pressures of oxygen of the Spred2-/- mice after reperfusion were significantly worse than those of WT mice (p < 0.01). Spred2-/- mice displayed more severe injuries than WT mice with increased neutrophil infiltration observed by a histological evaluation and flow cytometry (p < 0.001). This severe inflammation was inhibited by U0126. In addition, the rate of ERK1 activation was significantly higher in the lungs of Spred2-/- mice after reperfusion than in WT mice according to a Western blot analysis (p < 0.05). CONCLUSION: The activation of the ERK1/2 signaling pathway influences the severity of lung IRI, causing inflammation with neutrophil infiltration. SPRED2 may be a promising target for the suppression of lung IRI.

DOI： 10.1007/s00595-018-1696-x

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Iron chelation therapy is the main treatment for iron overload disease. Iron chelators were recently reported to be useful for cancer therapy; however, they cause side effects that make them difficult to use in some cancer patients. Thus, a novel oral iron chelator, super-polyphenol (SP), was developed for cancer therapy to decrease the side effects. SP is either water soluble or insoluble, and has different isoforms according to the number of side chains. Of these isoforms, water-soluble SP6 and SP10 appear to be the best candidates, as they have the strongest chelating abilities. In this study, we focused on the usefulness and safety of SP6 and SP10 as anti-cancer drugs, and examined their anti-cancer effects and toxicity. The results showed that SP6 and SP10 inhibited cancer cell proliferation by inducing apoptosis in HCT116, HSC-2, A549, and MCF-7 cancer cells. SP10 also inhibited tumor growth in an HCT116 xenograft model. SP6 and SP10 had no acute toxicities. An intravenous injection test revealed that SP6 and SP10 had better safety profiles than the iron chelator deferoxamine. In conclusion, SP is a novel oral iron chelator with anti-cancer effects and few adverse side effects. This is the first report of SP in the literature.

DOI： 10.18632/oncotarget.25973

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.healun.2018.01.509

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Recent studies have recognized the involvement of microRNAs (miRNAs) in the development of osteoporosis, which regulate the balance between osteogenesis and osteoclasis. In this study, we investigated the regulation by miRNA-133a-5p on the osteoblast differentiation-associated markers in the mouse osteoblast-like MC3T3-E1 cells by RUNX2. First, we manipulated the miRNA-133a level in the MC3T3-E1 cells with 20 or 40 nM miR-133a-5p mimics, miR-133a-5p inhibitor, or scramble miRNA. Then, we quantified with real-time polymerase chain reaction (qRT-PCR) the expression of Collagen I, osteocalcin (OCN), and osteopontin (OPN) in the miR-133a-5p-manipulated MC3T3-E1 cells. And the confocal microscopy was also utilized to confirm the regulation by miR-133a-5p on the expression of the three molecules. We also investigated the extracellular matrix (ECM) mineralization and the alkaline phosphatase (ALP) activity in the miR-133a-5p-manipulated MC3T3-E1 cells. In addition, we explored the possible targeting by miR-133a-5p on RUNX2, which was a well-recognized promoter to osteoblast differentiation, with luciferase reporter, qRT-PCR, and Western blotting assay. Results demonstrated that the miRNA-133a-5p mimics markedly reduced, whereas the miRNA-133a-5p inhibitor significantly promoted the expression of Collagen I, OCN, and OPN, the ECM mineralization, and the ALP activity in MC3T3-E1 cells. The alignment analysis demonstrated a high homology between miRNA-133a-5p and the 3' UTR of RUNX2. Moreover, the luciferase reporter assay demonstrated that miRNA-133a-5p targeted the 3' UTR of RUNX2, and inhibited the expression of RUNX2 in both mRNA and protein levels. In conclusion, we identified the inhibition by miRNA-133a-5p to the expression of osteoblast differentiation markers, to the ECM mineralization, and to the ALP activity in MC3T3-E1 cells, by targeting the 3' UTR of RUNX2. Our study suggests that miRNA-133a-5p might be an important target to inhibit osteoblast differentiation in osteoporosis.

DOI： 10.1089/dna.2017.3936

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Acute liver injury (ALI) is characterized by hepatocyte damage and inflammation. In the present study, we examined whether the absence of Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, influences ALI induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS). Compared to wild-type mice, Spred2-/- mice developed exacerbated liver injury represented by enhanced hepatocyte damage and inflammation. Enhanced ERK activation was observed in Spred2-/--livers, and the MEK/ERK inhibitor U0126 ameliorated ALI. Hepatic tumour necrosis factor α (TNFα) and interleukin (IL)-1β levels were increased in Spred-2-/--livers, and the neutralization of TNFα dramatically ameliorated ALI, which was associated with decreased levels of endogenous TNFα and IL-1β. When mice were challenged with D-GalN and TNFα, much severer ALI was observed in Spred2-/- mice with significant increases in endogenous TNFα and IL-1β in the livers. Immunohistochemically, Kupffer cells were found to produce TNFα, and isolated Kupffer cells from Spred2-/- mice produced significantly higher levels of TNFα than those from wild-type mice after LPS stimulation, which was significantly decreased by U0126. These results suggest that Spred2 negatively regulates D-GalN/LPS-induced ALI under the control of TNFα in Kupffer cells. Spred2 may present a therapeutic target for the treatment of ALI.

DOI： 10.1038/s41598-017-18380-0

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

The treatment of spinal cord injury (SCI) is currently a significant challenge. Hepatocyte growth factor (HGF) is a multipotent neurotrophic and neuroregenerative factor that can be beneficial for the treatment of SCI. However, immobilized HGF targeted to extracellular matrix may be more effective than diffusible, unmodified HGF. In this study, we evaluated the neurorestorative effects of an engineered HGF with a collagen biding domain (CBD-HGF). CBD-HGF remained in the spinal cord for 7 days after a single administration, while unmodified HGF was barely seen at 1 day. When a gelatin-furfurylamine (FA) hydrogel was applied on damaged spinal cord as a scaffold, CBD-HGF was retained in gelatin-FA hydrogel for 7 days, whereas HGF had faded by 1 day. A single administration of CBD-HGF enhanced recovery from spinal cord compression injury compared with HGF, as determined by motor recovery, and electrophysiological and immunohistochemical analyses. CBD-HGF alone failed to improve recovery from a complete transection injury, however CBD-HGF combined with gelatin-FA hydrogel promoted endogenous repair and recovery more effectively than HGF with hydrogel. These results suggest that engineered CBD-HGF has superior therapeutic effects than naïve HGF. CBD-HGF combined with hydrogel scaffold may be promising for the treatment of serious SCI.

DOI： 10.1038/s41598-018-19316-y

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Fibroblasts are a major component of cancer tissue and known to contribute to cancer progression. However, it remains unknown whether they are derived from local fibroblasts or of other origin. This study was designed to identify the contribution of local stromal cells to cancer stroma in human epithelial ovarian cancer. Seventy-six cases of surgically resected primary ovarian carcinoma (48 cases confined to the ovaries and 28 cases with distant metastases) and 17 cases of secondary ovarian tumor (e.g. colon cancer metastasized to the ovary) were enrolled in this study. The tissues were immunostained for forkhead box protein L2 (FOXL2), a transcription factor crucial for ovarian development and function, and markers for cancer-associated fibroblasts (CAFs) and inflammatory cells. Under normal condition, FOXL2 expression was restricted to ovarian stromal cells and some other types of cells in female genital tracts and never found in other sites of the body. FOXL2-positive cells were found in all primary and secondary tumors in the ovary, and were the dominant stromal cells in most cases. In contrast, only a few FOXL2-positive cells were found in peritoneal seeding sites of four serous carcinoma cases, and all the other tumors at extraovarian sites had no FOXL2-positive cells. FOXL2-positive cells in the ovarian lesion variably expressed CAFs markers, such as alpha-smooth muscle actin and fibroblast activating protein, as determined by double immunostaining. Background inflammation, but not histological subtype or origin of the neoplasm seemed to correlate with the proportion of FOXL2-positive cells. These results suggest that ovarian stromal cells are the main source of cancer stroma in the ovary but do not seem to move to distant sites via circulation together with tumor cells. Our results also support the hypothesis that cancer-associated fibroblasts may originate locally, which was previously demonstrated using animal models.

DOI： 10.1371/journal.pone.0205494

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Language：English   Publishing type：Research paper (scientific journal)  

Adequate iron levels are essential for human health. However, iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, iron depletion by the iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and iron depletion may be a novel therapeutic strategy to target CSCs.

DOI： 10.18632/oncotarget.21846

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media S.A.  

DOI： 10.3389/fimmu.2017.01524

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Sepsis is an infection-induced systemic inflammatory syndrome and a major cause of death for critically ill patients. Here, we examined whether the absence of Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, influences host defense against polymicrobial sepsis (PMS) induced by cecal ligation and puncture (CLP). Compared to wildtype mice, Spred2(-)/(-) mice exhibited higher survival rates with increased level of leukocyte infiltration and local chemokine production and reduced plasma and peritoneal bacterial loads after CLP. The MEK inhibitor U0126 significantly reduced LPS-induced chemokine production by Spred2(-)/(-) resident macrophages in vitro, and decreased CLP-induced leukocyte infiltration in vivo. Spred2(-)/(-)resident macrophages, but not neutrophils or elicited macrophages, exhibited increased phagocytic activity. Interestingly, surface expression of complement receptor 1/2 (CR1/2) was increased in Spred2(-)/(-) resident macrophages in response to lipopolysaccharide in a manner dependent on the ERK/MAPK pathway, and blocking CR1/2 in vivo resulted in reduced leukocyte infiltration and increased bacterial loads after CLP. Taken together, our results indicate that Spred2-deficiency protects mice from PMS via increased activation of the ERK/MAPK pathway and subsequent increase in innate immune responses. Thus, inhibiting Spred2 may present a novel means to prevent the development of PMS.

DOI： 10.1038/s41598-017-13204-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Macrophages are critical immune cells for the clearance of microbial pathogens and cellular debris from peripheral tissues. Macrophage inflammatory responses are governed by gene expression patterns, and these patterns are often subject to epigenetic control. Chromatin modifications, such as histone methylation, regulate gene accessibility in macrophages, and macrophage polarization is governed in part by the expression and function of chromatin-modifying enzymes. The histone methyltransferase mixed-lineage leukemia 1 (MLL1) preferentially modifies lysine residue 4 on the unstructured protein tail of histone H3. MLL1 expression and function have been shown to be governed by signal transduction pathways that are activated by inflammatory stimuli, such as NF-kappa B. Therefore, we sought to investigate the role of MLL1 in mediating macrophage inflammatory responses. Bone marrow-derived macrophages from mice with a targeted MLL1 gene knockout (Lys2-Cre(+/-) MLL1(fx/fx)) exhibited decreased proinflammatory gene expression with concurrent decreases in activating histone methylation. However, MLL1-deficient macrophages also exhibited increased phagocytic and bacterial killing activity in vitro. RNA profiling of MLL1-knockout macrophages identified numerous genes involved with inflammatory responses whose expression was altered in response to TLR ligands or proinflammatory cytokines, including STAT4. STAT4-dependent cytokines, such as type I IFNs were able to drive MLL1 expression in macrophages, and MLL1-knockout macrophages exhibited decreased activating histone methylation in the STAT4 promoter. These results implicate an important role for MLL1-dependent epigenetic regulation of macrophage antimicrobial functions.

DOI： 10.4049/jimmunol.1601272

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Background: Breast cancer is the most common cancer in Myanmar women. Revealing the hormonal receptor
status, human epidermal growth factor receptor 2 (HER2) and Ki-67 expression is useful for estimating patient
prognosis as well as determination of treatment strategy. However, immunohistochemical features and classification of
molecular subtypes in breast cancers from Myanmar remain unknown. Methods: The clinicopathological features of
91 breast cancers from Myanmar women were examined. Immunohistochemistry was performed on tissue specimens
with antibodies to estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki-67, cytokeratin (CK)5/6 and CK14.
Immunohistochemistry-based molecular subtyping was conducted. Results: Breast cancers in Myanmar women were
relatively large, high grade with frequent metastatic lymph nodes. Of the 91 patients, tumors with ER positive, PgR
positive, and HER2 positive were 57.1%, 37.4%, and 28.6%, respectively. The most prevalent subtype was luminal B
(HER2-) (39.6%), followed by HER2 (22.0%), triple negative (TN)-basal-like (12.1%), luminal A (11.0%), TN-null
(8.8%) and luminal B (HER2+) (6.6%). The mean Ki-67 expression of 91 cases was 33.9% (33.9% ± 19.2%) and the
median was 28% (range; 4%-90%). The mean Ki-67 expression of luminal A, luminal B, HER2 and TN-basal-like/
null was 7%, 30%, 40%, and 57%/43%, respectively. A higher Ki-67 expression significantly correlated with a higher
grade, larger size and higher stage of malignancy. Conclusions: We, for the first time, investigated the histopathological
features of breast cancers from Myanmar women. Myanmar breast cancers appeared to be aggressive in nature, as
evidenced by high frequency of poor-prognosis subtypes with high level of Ki-67 expression.

DOI： 10.22034/APJCP.2017.18.6.1617

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Human mammary tumor virus (HMTV) is 90-95% homologous to mouse mammary tumor virus (MMTV), one of the causal agents of murine mammary tumors. HMTV (MMTV-like) sequences were reported to be present in human breast cancers from several populations with a prevalence range of 0-78%; however, the prevalence of HMTV in breast cancers from Myanmar remains unknown.
Methods: Fifty-eight breast cancer samples from Myanmar women were examined in this study. DNA was isolated from formalin-fixed paraffin-embedded specimens, and HMTV envelope sequences were detected by semi-nested PCR. The sequence of the PCR products was also confirmed.
Results: Only 1.7% (1 of 58) of the breast cancers were positive for HMTV, and the sequence of PCR products was 98.9% identical to the reference HMTV sequence (GenBank accession No. AF243039). The tumor with HMTV was grade III invasive ductal carcinoma, 7.0 cm in size with lymph node metastasis (T3, N1, M0).
Conclusions: We, for the first time, investigated the presence of HMTV in Myanmar breast cancer patients. In accordance with other Asian studies, the prevalence of HMTV in Myanmar was quite low, supporting the hypothesis that Asian breast cancers have different etiologies than in Western countries, where HMTV is more prevalent.

DOI： 10.1186/s13027-017-0130-0

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Language：Japanese   Publisher：(公財)日本眼科学会  

緑内障に対する手術治療は流出路再建術,濾過手術,毛様体破壊/凝固術に大別される.理想的な効果と安全性を兼ね備えた術式はないが,その中で眼圧下降効果は濾過手術が優るといえる.濾過手術の一種である線維柱帯切除術は最も標準的な緑内障手術の一つであり,優れた眼圧下降効果を有する一方で,術後に過剰な創傷治癒に伴って眼圧コントロール不良となる症例が一定数存在し,重篤な術中・術後合併症もまれではない.したがって,緑内障手術成績のさらなる改善は緑内障診療において重要な命題であり,本総説では,この命題に取り組むべく,我々が多面的に行ってきた臨床研究および基礎研究について紹介し,その成果と新しい試みについて論じた.まず,臨床成績の解析から,白内障手術の既往および施行が線維柱帯切除術の手術成績に一定の影響を与えることが明らかとなった.また硝子体手術既往眼,緑内障手術既往眼は手術既往なしと比較して,ぶどう膜炎に伴う緑内障,血管新生緑内障,家族性アミロイドポリニューロパチーに伴う緑内障は一般的に原発開放隅角緑内障と比較して線維柱帯切除術の成績が不良であった.これらの危険因子は眼内環境に変化を及ぼし,その結果,線維柱帯切除術の創傷治癒に影響が及び,最終的に眼圧コントロールが不良となったと考えられる.次に,背景因子が眼内環境に及ぼした変化に焦点を当て,房水サイトカインに着目して解析を行った.白内障手術既往眼では術後1年以上経過してもinterleukin(IL)-6,IL-8,monocyte chemoattractant protein(MCP)-1などの炎症性サイトカインの濃度が高値であった.これらのサイトカイン濃度は互いに正の相関があるとともに,ぶどう膜炎に伴う緑内障や血管新生緑内障でさらに高値であり,複合的に創傷治癒に影響を与えていることが示唆された.このうち房水内MCP-1は線維柱帯切除術術後成績に影響を与える因子と確認された.さらに,眼内の環境変化が濾過胞に与える影響を詳細に観察するために,我々は三次元光干渉断層計を用いた定量的な濾過胞解析を行った.三次元的な解析によって線維柱帯切除術術後の強膜弁縁における開口部を同定し,術中所見からこれが濾過胞への房水流出路となっていることを確認した.前向き研究によって,この開口部の幅は時間経過とともに狭くなり将来的な眼圧コントロールに関係することが示唆されるとともに,房水内MCP-1濃度と相関していることが明らかとなった.最後に,線維柱帯切除術術後の創傷治癒機転を細胞レベルで理解するために,マクロファージと結膜線維芽細胞を用いた細胞生物学的な実験を行った.創傷治癒機転において,マクロファージなどの関与によって線維芽細胞が筋線維芽細胞化することが重要であることが分かっている.この変化をROCK阻害薬やエピジェネティック薬が抑制することを見出した.また,2光子顕微鏡を用いた生体イメージングにより,手術によって結膜下の炎症細胞の動態は大きく影響を受けることが確認された.眼内環境の病的シフトをリスクの低い状態に近づけることを目的とした抗MCP-1治療やレセプターであるCCR2の阻害薬は,緑内障手術成績改善の試みの新たな糸口となる可能性を秘めていると考えられた.(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Objective: We aimed to determine the distribution of tumor-associated macrophages (TAMs) in the development of tongue squamous cell carcinoma (SCC) and to elucidate the role of TAMs in the progression of tongue SCC. Methods: The expression of the macrophage markers nitric oxide synthase, Retnla, and mannose receptor 1 in the development of tongue SCC was longitudinally observed using real-time quantitative polymerase chain reaction. Additionally, an immunohistochemical study using an anti-mannose receptor (MR) antibody was performed. Results: The numbers of both of M1 and M2 macrophages in the tongues of mice treated with 4-nitroquinoline-1-oxide (4NQO) were significantly lower compared with those of normal tongues. The cyclo-oxygenase-2 (COX-2) inhibitor did not prevent cancer progression and did not affect the total number of macrophages in the tongues of 4NQO-treated mice. In the immunohistochemical studies, MR staining was observed in lymphangio-endothelium in the subepithelial area of the tongues. The staining intensity of the MR was significantly stronger in the 4NQO-treated mice compared with that in control mice and 4NQO-treated mice treated with the COX-2 inhibitor. Conclusion: TAMs may not contribute to the development of 4NQO-induced tongue SCC. MR expression is associated with the progression of 4NQO-induced tongue SCC. (C) 2017 S. Karger AG, Basel

DOI： 10.1159/000477301

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Language：Japanese   Publisher：(一社)日本病理学会  

多房化した肉眼形態を示し、術前診断が困難であったsex cord tumor with annular tubules(SCTAT)の1例を経験したので報告する。症例は月経不順でホルモン治療中の20代女性。増大傾向の右卵巣腫瘍を指摘され、臨床的には境界悪性ないし悪性の粘液性腫瘍が疑われ手術が行われた。腫瘍は多房性嚢胞性、肥厚した壁の部分には腫瘍細胞の輪状細管を含む胞巣を認めた。免疫染色ではinhibin-αとFOXL2が陽性、遺伝子解析ではFOXL2(C134W)変異はなく、SCTATと診断した。(著者抄録)

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Language：Japanese   Publisher：(一社)日本病理学会  

17歳、男性。てんかん発作を幼少期より繰り返していた。3歳時の頭部CTでは病変を指摘されなかったが、13歳時に左中前頭回の脳表に石灰化を伴う病変を認めた。発作頻度が増したため、17歳時に病変とその直下のてんかん焦点を含む左前頭葉部分切除術が施行された。脳表側では砂粒体と渦巻き状に紡錘形細胞が認められ、移行性髄膜腫であった。大脳側では血管が網目状に増生し、血管周囲には髄膜皮細胞が取り巻く髄膜血管腫症であった。症状や画像の経過より髄膜血管腫症が先行し、その後髄膜腫が合併したと考えられた。(著者抄録)

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Language：Japanese   Publisher：Okayama Medical Association  

DOI： 10.4044/joma.129.195

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Other Link： https://www.jstage.jst.go.jp/article/joma/129/3/129_195/_pdf

Language：Japanese   Publisher：(公社)日本臨床細胞学会  

背景:Gangliocytic paraganglioma(GP)は、十二指腸乳頭部に好発するまれな腫瘍で、主として粘膜下に存在するため、生検による確定診断は困難なことが多い。EUS-FNAは術前診断の有効な方法として期待されるが、その報告は少ない。症例:60歳代、男性。タール便を主訴に上部消化管内視鏡が施行された。生検では十二指腸粘膜のみしか得られなかった。EUS-FNA検体では、細顆粒状クロマチンを有する短紡錘形〜類円形の核をもつ紡錘形細胞に加え、少数ながら核小体の目立つ大型細胞も認められた。多彩な細胞像を呈し、核所見などから神経内分泌系の腫瘍が疑われた。膵十二指腸切除検体では十二指腸乳頭部の近傍に粘膜下腫瘍が認められた。組織学的に腫瘍は、Zellballen配列をとる上皮様細胞、明瞭な核小体をもつ神経節細胞様細胞、束状の紡錘形細胞(支持細胞)の3成分から構成されていた。最終的にGPと病理診断された。結論:EUS-FNA検体では必ずしも3成分の細胞が採取されない可能性がある。しかし、3成分の細胞が正しく採取され、さらにセルブロックの免疫組織化学的検討を加えれば、診断は可能と思われた。(著者抄録)

DOI： 10.5795/jjscc.55.376

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Rapid and adequate mucosal healing is important for a remission of ulcerative colitis (UC) patients. Here, we examined whether Spred2, a member of the Sprouty-related EVH1-domain-containing proteins that inhibit the Ras/Raf/ERK pathway, plays a role in colonic mucosal homeostasis and inflammation by using Spred2 knockout (KO) mice. We first detected increased epithelial cell proliferation and cadherin 1 expression in the colon of naive Spred2 KO mice compared to wild-type mice. Interestingly, Spred2 KO mice were resistant to dextran sulfate sodium (DSS)-induced acute colitis as indicated by lower levels of body weight loss and disease activity index. Histologically, epithelial cell injury and inflammation were milder in the colonic mucosa of Spred2 KO mice on day 3 and almost undetectable by day 8. Experiments with bone chimeric mice indicated that Spred2 deficiency in non-hematopoietic cells was responsible for the reduced sensitivity to DSS. Finally, Spred2 KO mice developed significantly fewer tumors in response to azoxymethane plus DSS. Taken together, our results demonstrate, for the first time, that Spred2 plays an important role in the regulation of colonic epithelial cell proliferation and inflammation by potentially down-regulating the activation of ERK. Thus, Spred2 may be a new therapeutic target for the treatment of UC.

DOI： 10.1038/srep37531

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

The objective of this study was to observe the distribution of regulatory T cells (Tregs) in the development of tongue squamous cell carcinoma (SCC) and to determine the role of Tregs in the progression of tongue SCC. A mouse model of 4-nitroquinoline-1-oxide (4NQO)-induced-tongue SCC was established. The expression of Forkhead box P3 (Foxp3), interleukin 10, transforming growth factor-beta, chemokine CC motif ligands 17, 20, and CC chemokine receptor 4 was determined using real-time quantitative polymerase chain reaction. Foxp3 expression was also analyzed using immunohistochemistry. The results were compared with those of control mice and of 4NQO-treated mice treated with a cyclooxygenase-2 (COX-2) inhibitor. Well to moderately differentiated tongue SCC was induced in all of the experimental mice. The amount of Tregs of the experimental mice was over 10 times as much as control mice at the early stage of tumor progression. COX-2 inhibitor did not prevent the progression of tongue SCC and did not reduce the total amount of Tregs. Tregs function at the early stage of the development of tongue SCC, and it may be effective to suppress Tregs at the early stage of tumor progression for the treatment and/or prevention of tongue SCC.

DOI： 10.1007/s00262-016-1902-x

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objectives: Influenza A virus causes acute respiratory infections that induce annual epidemics and occasional pandemics. Although a number of studies indicated that the virus-induced intracellular signaling events are important in combating influenza virus infection, the mechanism how specific molecule plays a critical role among various intracellular signaling events remains unknown. Raf/MEK/extracellular signal-regulated kinase cascade is one of the key signaling pathways during influenza virus infection, and the Sprouty-related Ena/vasodilator-stimulated phos-phoprotein homology 1-domain-containing protein has recently been identified as a negative regulator of Raf-dependent extracellular signal-regulated kinase activation. Here, we examined the role of Raf/MEK/extracellular signal-regulated kinase cascade through sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein in influenza A viral infection because the expression of sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein was significantly enhanced in human influenza viral-induced pneumonia autopsy samples.
Design: Prospective animal trial.
Setting: Research laboratory.
Subjects: Wild-type and sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 knockout mice inoculated with influenza A.
Interventions: Wild-type or sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 knockout mice were infected by intranasal inoculation of influenza A (A/PR/8). An equal volume of phosphate-buffered saline was inoculated intranasally into mock-infected mice.
Measurements and Main Results: Influenza A infection of sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 knockout mice led to higher mortality with greater viral load, excessive inflammation, and enhanced cytokine production than wild-type mice. Administration of MEK inhibitor, U0126, improved mortality and reduced both viral load and cytokine levels. Furthermore, bone marrow chimeras indicated that influenza A-induced lung pathology was most severe when sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 expression was lacking in nonimmune cell populations. Furthermore, microarray analysis revealed knockdown of sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 led to enhanced phosphatidylinositol 3-kinase signaling pathway, resulting that viral clearance was regulated by sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 expression through the phosphatidylinositol 3-kinase signaling pathway in murine lung epithelial cells.
Conclusions: These data support an important function of sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 in controlling influenza virus-induced pneumonia and viral replication. Sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 may be a novel therapeutic target for controlling the immune response against influenza influenza A virus infection.

DOI： 10.1097/CCM.0000000000001562

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FRONTIERS MEDIA SA  

Monocyte chemoattractant protein-1 (MCP-1)/CCL2 plays an important role in the initiation and progression of cancer. We previously reported that in 4T1 murine breast cancer, non-tumor stromal cells, including macrophages, were the major source of MCP-1. In the present study, we analyzed the potential mechanisms by which MCP-1 is upregulated in macrophages infiltrating 4T1 tumors. We found that cell free culture supernatants of 4T1 cells (4T1-sup) markedly upregulated MCP-1 production by peritoneal inflammatory macrophages. 4T1-sup also upregulated other MCPs, such as MCP-3/CCL7 and MCP-5/CCL12, but modestly upregulated neutrophil chemotactic chemokines, such as KC/CXCL1 or MIP-2/CXCL2. Physicochemical analysis indicated that an approximately 2-3 kDa 4T1 cell product was responsible for the capacity of 4T1-sup to upregulate MCP-1 expression by macrophages. A neutralizing antibody against granulocyte/macrophage colony stimulating factor (GM-CSF), but not macrophage CSF, almost completely abrogated MCP-1-inducing activity of 4T1-sup, and recombinant GM-CSF potently upregulated MCP-1 production by macrophages. The expression levels of GM-CSF in 4T1 tumors in vivo were higher than other tumors, such as Lewis lung carcinoma. Treatment of mice with anti-GM-CSF antibody significantly reduced the growth of 4T1 tumors at the injection sites but did not reduce MCP-1 production or lung metastasis in tumor-bearing mice. These results indicate that 4T1 cells have the capacity to directly upregulate MCP-1 production by macrophages by releasing GM-CSF; however, other mechanisms are also involved in increased MCP-1 levels in the 4T1 tumor microenvironment.

DOI： 10.3389/fimmu.2016.00002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Human hepatocellular carcinoma (HCC) is known to have a poor prognosis. Sorafenib, a molecular targeted drug, is most commonly used for HCC treatment. However, its effect on HCC is limited in clinical use and therefore new strategies regarding sorafenib treatment are required. Iron overload is known to be associated with progression of chronic hepatitis and increased risk of HCC. We previously reported that iron depletion inhibited cancer cell proliferation and conversely induced angiogenesis. Indeed iron depletion therapy including iron chelator needs to be combined with anti-angiogenic drug for its anti-cancer effect. Since sorafenib has an anti-angiogenic effect by its inhibitory targeting VEGFR, we hypothesized that sorafenib could complement the anti-cancer effect of iron depletion. We retrospectively analyzed the relationship between the efficacy of sorafenib and serum iron-related markers in clinical HCC patients. In clinical cases, overall survival was prolonged in total iron binding capacity (TIBC) high- and ferritin low-patients. This result suggested that the low iron-pooled patients, who could have a potential of more angiogenic properties in/around HCC tumors, could be adequate for sorafenib treatment. We determined the effect of sorafenib (Nexavar (R)) and/or deferasirox (EXJADE (R)) on cancer cell viability, and on cell signaling of human hepatocarcinoma HepG2 and HLE cells. Both iron depletion by deferasirox and sorafenib revealed insufficient cytotoxic effect by each monotherapy, however, on the basis of increased angiogenesis by iron depletion, the addition of deferasirox enhanced anti-proliferative effect of sorafenib. Deferasirox was confirmed to increase vascular endothelial growth factor (VEGF) secretion into cellular supernatants by ELISA analysis. In in vivo study sorafenib combined with deferasirox also enhanced sorafenib-induced apoptosis. These results suggested that sorafenib combined with deferasirox could be a novel combination chemotherapy for HCC.

DOI： 10.1080/15384047.2016.1177677

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：IOP PUBLISHING LTD  

A multifunctional biomaterial with the capacity bond to hard tissues, such as bones and teeth, is a real need for medical and dental applications in tissue engineering and regenerative medicine. Recently, we created phosphorylated-pullulan (PPL), capable of binding to hydroxyapatite in bones and teeth. In the present study, we employed PPL as a novel biocompatible material for bone engineering. First, an in vitro evaluation of the mechanical properties of PPL demonstrated both PPL and PPL/beta-TCP composites have higher shear bond strength than materials in current clinical use, including polymethylmethacrylate (PMMA) cement and a-tricalcium phosphate (TCP) cement, Biopex-R. Further, the compressive strength of PPL/beta-TCP composite was significantly higher than Biopex-R. Next, in vivo osteoconductivity of PPL/beta-TCP composite was investigated in a murine intramedular injection model. Bone formation was observed 5 weeks after injection of PPL/beta-TCP composite, which was even more evident at 8 weeks; whereas, no bone formation was detected after injection of PPL alone. We then applied PPL/beta-TCP composite to a rabbit ulnar bone defect model and observed bone formation comparable to that induced by Biopex-R. Implantation of PPL/beta-TCP composite induced new bone formation at 4 weeks, which was remarkably evident at 8 weeks. In contrast, Biopex-R remained isolated from the surrounding bone at 8 weeks. In a pig vertebral bone defect model, defects treated with PPL/beta-TCP composite were almost completely replaced by new bone; whereas, PPL alone failed to induce bone formation. Collectively, our results suggest PPL/beta-TCP composite may be useful for bone engineering.

DOI： 10.1088/1748-6041/10/6/065009

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BACKGROUND: Early growth response-1 (Egr-1) has been shown to be a trigger-switch transcription factor that is involved in lung ischemia-reperfusion injury (IRI). METHODS: Mouse lung transplants were performed in wild-type (WT) C57BL/6 and Egr1-knockout (KO) mice in the following donor → recipient combinations: WT → WT, KO → WT, WT → KO, and KO → KO to determine whether the presence of Egr-1 in the donor or recipient is the most critical factor for IRI. Pulmonary grafts were retrieved after 18 hours of ischemia after 4 hours of reperfusion. We analyzed graft function by analyzing arterial blood gas and histology in each combination and assessed the effects of Egr1 depletion on inflammatory cytokines that are regulated by Egr-1 as well on polymorphonuclear neutrophil (PMN) infiltration. RESULTS: Deletion of Egr1 improved pulmonary graft function in the following order of donor → recipient combinations: WT → WT < WT → KO < KO → WT < KO → KO. Polymerase chain reaction assays for Il1B, Il6, Mcp1, Mip2, Icam1, and Cox2 showed significantly lower expression levels in the KO → KO group than in the other groups. Immunohistochemistry demonstrated clear Egr-1 expression in the nuclei of pulmonary artery endothelial cells and PMN cytoplasm in the WT grafts. Flow cytometry analysis showed that Egr1 deletion reduced PMN infiltration and that the extent of reduction correlated with graft function. CONCLUSIONS: Both graft and recipient Egr-1 played a role in lung IRI, but the graft side contributed more to this phenomenon through regulation of PMN infiltration. Donor Egr-1 expression in pulmonary artery endothelial cells may play an important role in PMN infiltration, which results in IRI after lung transplantation.

DOI： 10.1097/TP.0000000000000783

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Introduction: Provision for the emergence of an influenza pandemic is an urgent issue. The discovery of a novel anti-influenza therapeutic approach would increase the effectiveness of traditional virus-based strategies. This study was undertaken to evaluate the therapeutic effects of anti-high mobility group box-1 (HMGB1) monoclonal antibody (mAb) treatment on influenza A virus (H1N1)-induced pneumonia in mice.
Methods: Nine-week-old male C57BL/6 mice were inoculated with H1N1, then anti HMGB1 mAb or control mAb were administered intravenously at 1, 24 and 48 hours after H1N1 inoculation and the survival rate was analyzed. Lung lavage and histopathological analysis were performed on days 3, 5, 7 and 10 after inoculation.
Results: Anti-HMGB1 mAb significantly improved the survival rate of H1N1-inoculated mice (1 out of 15 versus 8 out of 15 deaths in the anti-HMGB1 mAb-treated group versus the control mAb-treated group, p &lt; 0.01), although the treatment did not affect virus propagation in the lungs. The treatment also significantly attenuated histological changes and neutrophil infiltration in the lungs of H1N1-inoculated mice. This was associated with inhibition of HMGB1 and suppression of inflammatory cytokine/chemokine expression and oxidative stress enhancement, which were observed in H1N1-inoculated mice. The expression of receptor for advanced glycation end products and nuclear factor kappa B was attenuated by the treatment.
Conclusions: Anti-HMGB1 mAb may provide a novel and effective pharmacological strategy for severe influenza virus infection in humans by reducing the inflammatory responses induced by HMGB1.

DOI： 10.1186/s13054-015-0983-9

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BACKGROUND CONTEXT: Plasma-mediated radiofrequency-based ablation (coblation) is an electrosurgical technique currently used for tissue removal in a wide range of surgical applications, including lumbar microdiscectomy. In vitro and in vivo studies have shown the technique to alter the expression of inflammatory cytokines in the disc, increasing the levels of interleukin-8 (IL-8), which may promote maturation and remodeling of the disc matrix. PURPOSE: To better understand the effect of coblation treatment, this study characterizes the temporal and spatial pattern of healing after stab injury to the rabbit intervertebral disc, with and without plasma-mediated radiofrequency treatment. PATIENT SAMPLE: A total of 23 New Zealand white rabbits. STUDY DESIGN: Annular and nuclear stab injuries. OUTCOME MEASURES: Sandwich enzyme-linked immunosorbent assay evaluated the concentrations of cytokines tumor necrosis factor-α, IL-1β, and IL-8. Histopathologic evaluations were performed on whole discs and end plates. Tissue sections were stained with Safranin-O to evaluate nucleus pulposus and annulus fibrosus proteoglycan content and with Alcian blue for extracellular proteoglycan content. Intradiscal leakage pressure was evaluated by injecting methylene blue dye into the nucleus. METHODS: Animals underwent annular and nuclear stab injuries on three consecutive lumbar discs (L2-L3 to L4-L5). The three levels were randomly assigned into one of the three groups for treatment with a plasma-mediated radiofrequency ablation device (TOPAZ; ArthroCare Corp., Austin, TX, USA): active treatment of the nucleus only (SN); active treatment of both nucleus and annulus (SNA); sham treatment. Unstabbed/untreated discs from L5-L6 (n=5) served as normal controls. Animals were euthanized at 4, 8, and 28 days postsurgery. RESULTS: Tumor necrosis factor-α was detected in sham discs at 4 and 8 days, but not in coblation groups (SN or SNA); IL-1β was below detection in all three treatment groups. Interleukin-8 levels increased in all treatment groups at 4 and 8 days compared with normal control, peaking at 4th day for sham and SN groups and 8th day (p>.3) for the SNA group (a 2.5-fold increase). Pressure measurements revealed higher leakage in the SN group, but no statistically significant differences. Histopathology showed higher proteoglycan production by 28 days in the SNA and SN groups compared with sham. All three treatment groups showed ruptured annular fibers from the stab injury, but maintained the overall architecture. Remnants of notochordal tissue within the nucleus were evident in all treatment groups at 4 and 8 days, but were only found in sham group by 28 days. At this time, unlike the normal or sham controls, the nucleus of SN and SNA discs had fibrocartilaginous tissue with chondrocyte-like cells. Significant differences in the disc architecture grade were only noted when comparing normal controls with other groups by 28 days (p<.001). CONCLUSIONS: Plasma-mediated radiofrequency ablation appears to have an anabolic effect on disc cells, stimulating proteoglycan and IL-8 production and maintaining annulus architecture. Coblation treatment appears to reduce cellular response to proinflammatory stimuli and restore overall disc architecture that may prove beneficial in a number of degenerative disc paradigms. Further studies are encouraged to investigate the therapeutic effect of the technique.

DOI： 10.1016/j.spinee.2014.04.010

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2014-3585

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background: Acute respiratory distress syndrome (ARDS) is a severe and life-threatening acute lung injury (ALI) that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK) pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred)-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK)-MAPK pathway, in lipopolysaccharide (LPS)-induced acute lung inflammation.
Methods: Wild-type (WT) mice and Spred-2(-/-) mice were exposed to intratracheal LPS (50 mu g in 50 mu L PBS) to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2(-/-) mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells.
Results: LPS- induced acute lung inflammation was significantly exacerbated in Spred-2(-/-) mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-alpha, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in Spred-2(-/-) mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells.
Conclusions: The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls the development of LPS-induced lung inflammation by negatively regulating the ERK-MAPK pathway. Thus, Spred-2 may represent a therapeutic target for the treatment of ALI.

DOI： 10.1371/journal.pone.0108914

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Language：Japanese   Publisher：(株)文光堂  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Chemokine (C-C motif) receptor 8 (CCR8), the chemokine receptor for chemokine (C-C motif) ligand 1 (CCL1), is expressed in T-helper type-2 lymphocytes and peritoneal macrophages (PM phi) and is involved in various pathological conditions, including peritoneal adhesions. However, the role of CCR8 in inflammatory responses is not fully elucidated. To investigate the function of CCR8 in macrophages, we compared cytokine secretion from mouse PM phi or bone marrow-derived macrophages (BMM phi) stimulated with various Toll-like receptor (TLR) ligands in CCR8 deficient (CCR8(-/-)) and wild-type (WT) mice. We found that CCR8(-/-) PM phi demonstrated attenuated secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10 when stimulated with lipopolysaccharide (LPS). In particular, LPS-induced IL-10 production absolutely required CCR8. CCR8-dependent cytokine secretion was characteristic of PM phi but not BMM phi. To further investigate this result, we selected the small molecule compound R243 from a library of compounds with CCR8-antagonistic effects on CCL1-induced Ca2+ flux and CCL1-driven PM phi aggregation. Similar to CCR8(-/-) PM phi, R243 attenuated secretion of TNF-alpha, IL-6, and most strikingly IL-10 from WT PM phi, but not BMM phi. CCR8(-/-)PM phi and R243-treated WT PM phi both showed suppressed c-jun N-terminal kinase activity and nuclear factor-kappa B signaling after LPS treatment when compared with WT PM phi. A c-Jun signaling pathway inhibitor also produced an inhibitory effect on LPS-induced cytokine secretion that was similar to that of CCR8 deficiency or R243 treatment. As seen in CCR8(-/-) mice, administration of R243 attenuated peritoneal adhesions in vivo. R243 also prevented hapten-induced colitis. These results are indicative of cross talk between signaling pathways downstream of CCR8 and TLR-4 that induces cytokine production by PMQ. Through use of CCR8(-/-) mice and the new CCR8 inhibitor, R243, we identified a novel macrophage innate immune response pathway that involves a chemokine receptor.

DOI： 10.1371/journal.pone.0094445

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Osteochondral injuries remain difficult to repair. We developed a novel photo-cross-linkable furfurylamine-conjugated gelatin (gelatin-FA). Gelatin-FA was rapidly cross-linked by visible light with Rose Bengal, a light sensitizer, and was kept gelled for 3 weeks submerged in saline at 37 degrees C. When bone marrow-derived stromal cells (BMSCs) were suspended in gelatin-FA with 0.05% Rose Bengal, approximately 87% of the cells were viable in the hydrogel at 24 h after photo-cross-linking, and the chondrogenic differentiation of BMSCs was maintained for up to 3 weeks. BMP4 fusion protein with a collagen binding domain (CBD) was retained in the hydrogels at higher levels than unmodified BMP4. Gelatin-FA was subsequently employed as a scaffold for BMSCs and CBD-BMP4 in a rabbit osteochondral defect model. In both cases, the defect was repaired with articular cartilage-like tissue and regenerated subchondral bone. This novel, photo-cross-linkable gelatin appears to be a promising scaffold for the treatment of osteochondral injury.

DOI： 10.1038/srep04457

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

The induction of leukemic cell differentiation is a hopeful therapeutic modality. We studied the effects of monochloramine (NH2Cl) on erythroleukemic K562 cell differentiation, and compared the effects observed with those of U0126 and staurosporine, which are known inducers of erythroid and megakaryocytic differentiation, respectively. CD235 (glycophorin) expression, a marker of erythroid differentiation, was significantly increased by NH2Cl and U0126, along with an increase in c mRNA levels. Other erythroid markers such as. gamma-globin and CD71 (transferrin receptor) were also increased by NH2Cl and U0126. In contrast, CD61 (integrin beta 3) and CD42b (GP1b alpha) expression, markers of megakaryocytic differentiation, was increased by staurosporine, but did not change significantly by NH 2 Cl and U0126. NH2Cl retarded cell proliferation without a marked loss of viability. When ERK phosphorylation (T202/ Y204) and CD235 expression were compared using various chemicals, a strong negative correlation was observed (r =-0.76). Paradoxically, NH2Cl and staurosporine, but not U0126, induced large cells with multiple or lobulated nuclei, which was characteristic to megakaryocytes. NH 2 Cl increased the mRNA levels of gata1 and scl, decreased that of gata2, and did not change those of pu.1 and klf1. The changes observed in mRNA expression were different from those of U0126 or staurosporine. These results suggest that NH2Cl induces the bidirectional differentiation of K562. Oxidative stress may be effective in inducing leukemic cell differentiation.

DOI： 10.3109/10715762.2013.865840

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

High-throughput screening was performed as a phenotypic screening on clinically relevant human mesenchymal stem cells to identify small molecules that affect stem cell fate. From a library of pharmacologically active small molecules, we identified kaempferol, which is a natural flavonol, with a high osteogenic activity. Kaempferol achieved the highest levels of bone-specific markers among the chemicals tested in vitro. The osteogenic activity of kaempferol was the same as that of ipriflavone, which is a synthetic isoflavone, in ovariectomized mouse experiments. Considering that kaempferol is present in various foods such as vegetables and fruits, it will be useful as a new preventive medicine for osteoporosis. (C) 2013 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jff.2013.10.013

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Introduction: Galectin-9 ameliorates various inflammatory conditions including autoimmune diseases by regulating T cell and macrophage/dendritic cell (DC) functions. However, the effect of galectin-9 on polymicrobial sepsis has not been assessed.Methods: We induced polymicrobial sepsis by cecal ligation and puncture (CLP) in mice. The survival rate was compared between galectin-9- and PBS-treated CLP mice. An ELISA was used to compare the levels of various cytokines in the plasma and culture supernatants. Fluorescence-activated cell sorting analysis was further performed to compare the frequencies of subpopulations of spleen cells.Results: Galectin-9 exhibited a protective effect in polymicrobial sepsis as demonstrated in galetin-9 transgenic mice and therapeutic galectin-9 administration. In contrast, such effect was not observed in nude mice, indicating the involvement of T cells in galectin-9-mediated survival prolongation. Galectin-9 decreased TNFα, IL-6, IL-10 and, high mobility group box 1 (HMGB1) and increased IL-15 and IL-17 plasma and spleen levels. Galectin-9 increased the frequencies of natural killer T (NKT) cells and PDCA-1+ CD11c+ macrophages (pDC-like macrophages) but did not change the frequency of CD4 or CD8 T cells, γδT cells or conventional DC. As expected, galectin-9 decreased the frequency of Tim-3+ CD4 T cells, most likely Th1 and Th17 cells. Intriguingly, many spleen NK1.1+ NKT cells and pDC-like macrophages expressed Tim-3. Galectin-9 increased the frequency of Tim-3-expressing NK1.1+ NKT cells and pDC-like macrophages. Galectin-9 further increased IL-17+ NK1.1+ NKT cells.Conclusion: These data suggest that galectin-9 exerts therapeutic effects on polymicrobial sepsis, possibly by expanding NKT cells and pDC-like macrophages and by modulating the production of early and late proinflammatory cytokines. © 2013 Kadowaki et al.; licensee BioMed Central Ltd.

DOI： 10.1186/cc13147

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Oxaliplatin-based chemotherapy is widely used for advanced colorectal cancer treatment, but it occasionally induces liver injury that is characterized histologically by sinusoidal dilatation, hepatic plate atrophy and/or venular obstruction. Most of the patients do not reveal apparent radiological abnormalities, however. Here, we report the case of a 47-year-old man with a radiologically detectable mass-forming oxaliplatin-induced sinusoidal injury that mimicked multiple liver tumors. These mass lesions were found on computed tomography images after the administration of six cycles of folinic acid, fluorouracil and oxaliplatin therapy as adjuvant chemotherapy for Stage III rectal cancer. The patient had to undergo liver resection because imaging studies could not exclude metastases. The histological examination revealed that a resected mass lesion was composed of severe sinusoidal dilatation. Milder dilatation was also seen in the surrounding parenchyma. We diagnosed the patient as having an oxaliplatin-induced sinusoidal injury with severe deviation. As oxaliplatin is a standard agent in colorectal cancer therapy today, all clinicians and pathologists should be aware of such non-neoplastic lesions as one of the rare differential diagnoses of metastatic liver tumor, to prevent overtreatment.

DOI： 10.1093/jjco/hyt113

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Language：Japanese   Publisher：日本臨床外科学会  

症例は80歳,男性.直腸S状部癌の精査目的CT検査,MRI検査にて回腸腸間膜に長径12cmの一部に石灰化を伴い造影効果のある充実性成分を伴う嚢胞性腫瘤を認めた.小腸腸間膜嚢胞腺癌,重複腸管,変性したGIST等を鑑別診断とし手術を行った.腫瘤は回腸末端から40から50cmの腸間膜に位置し浸潤傾向はなく腸管切除することなく核出術にて完全切除を行えた.摘出した腫瘤は13×6×5cm,256gで病理検査にて充実性腫瘤部に癌細胞を認め他部位の嚢胞壁には正常の円柱上皮,高円柱状異型細胞への移行像を認め嚢胞腺癌と診断された.腸間膜嚢胞に発生する腸間膜嚢胞腺癌は極めてまれな疾患であるが,今回われわれは直腸S状部癌の術前精査にて偶然発見された小腸腸間膜嚢胞腺癌の1例を経験したので若干の文献的考察を加え報告する.(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J03156&link_issn=&doc_id=20130507160021&doc_link_id=10.3919%2Fjjsa.74.968&url=https%3A%2F%2Fdoi.org%2F10.3919%2Fjjsa.74.968&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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DOI： 10.1097/ALN.0b013e31827e3c53

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1097/ALN.0b013e31827e3c53

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OBJECTIVES:: Influenza virus infections can cause severe acute lung injury leading to significant morbidity and mortality. Thioredoxin-1 is a redox-active defensive protein induced in response to stress conditions. Animal experiments have revealed that thioredoxin-1 has protective effects against various severe disorders. This study was undertaken to evaluate the protective effects of recombinant human thioredoxin-1 administration on influenza A virus (H1N1)-induced acute lung injury in mice. DESIGN:: Prospective animal trial. SETTING:: Research laboratory. SUBJECTS:: Nine-week-old male C57BL/6 mice inoculated with H1N1. INTERVENTION:: The mice were divided into a vehicle-treated group and recombinant human thioredoxin-1-treated group. For survival rate analysis, the vehicle or recombinant human thioredoxin-1 was administered intraperitoneally every second day from day-1 to day 13. For lung lavage and pathological analyses, vehicle or recombinant human thioredoxin-1 was administered intraperitoneally on days-1, 1, and 3. MEASUREMENTS AND MAIN RESULTS:: Lung lavage and pathological analyses were performed at 24, 72, and 120 hrs after inoculation. The recombinant human thioredoxin-1 treatment significantly improved the survival rate of H1N1-inoculated mice, although the treatment did not affect virus propagation in the lung. The treatment significantly attenuated the histological changes and neutrophil infiltration in the lung of H1N1-inoculated mice. The treatment significantly attenuated the production of tumor necrosis factor-α and chemokine (C-X-C motif) ligand 1 in the lung and oxidative stress enhancement, which were observed in H1N1-inoculated mice. H1N1 induced expressions of tumor necrosis factor-α and chemokine (C-X-C motif) ligand 1 in murine lung epithelial cells MLE-12, which were inhibited by the addition of recombinant human thioredoxin-1. The recombinant human thioredoxin-1 treatment started 30 mins after H1N1 inoculation also significantly improved the survival of the mice. CONCLUSIONS:: Exogenous administration of recombinant human thioredoxin-1 significantly improved the survival rate and attenuated lung histological changes in the murine model of influenza pneumonia. The protective mechanism of thioredoxin-1 might be explained by its potent antioxidative and anti-inflammatory actions. Consequently, recombinant human thioredoxin-1 might be a possible pharmacological strategy for severe influenza virus infection in humans. © 2013 by the Society of Critical Care Medicine and Lippincott Williams &amp
Wilkins.

DOI： 10.1097/CCM.0b013e3182676352

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Language：Japanese   Publisher：(一社)日本病理学会  

症例は妊娠中の20代女性。高度のネフローゼ症候群を呈し、腎生検が行われた。組織学的に糸球体の腫大と管内への炎症細胞浸潤を認めた。免疫染色では有意な所見は得られなかったが、組織化学的に糸球体でplasmin活性が認められ、溶連菌感染後急性糸球体腎炎と考えられた。本例の鑑別診断においてplasmin活性の酵素組織化学的所見が意義あると考えられた。文献的考察も加えて報告する。(著者抄録)

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Language：Japanese  

DOI： 10.4044/joma.125.109

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Language：English   Publishing type：Research paper (scientific journal)  

MCP-1/CCL2 plays an important role in the initiation and progression of cancer. Since tumor cells produce MCP-1, they are considered to be the main source of this chemokine. Here, we examined whether MCP-1 produced by non-tumor cells affects the growth and lung metastasis of 4T1 breast cancer cells by transplanting them into the mammary pad of WT or MCP-1(-/-) mice. Primary tumors at the injected site grew similarly in both mice; however, lung metastases were markedly reduced in MCP-1(-/-) mice, with significantly longer mouse survival. High levels of MCP-1 mRNA were detected in tumors growing in WT, but not MCP-1(-/-) mice. Serum MCP-1 levels were increased in tumor-bearing WT, but not MCP-1(-/-) mice. Transplantation of MCP-1(-/-) bone marrow cells into WT mice did not alter the incidence of lung metastasis, whereas transplantation of WT bone marrow cells into MCP-1(-/-) mice increased lung metastasis. The primary tumors of MCP-1(-/-) mice consistently developed necrosis earlier than those of WT mice and showed decreased infiltration by macrophages and reduced angiogenesis. Interestingly, 4T1 cells that metastasized to the lung constitutively expressed elevated levels of MCP-1, and intravenous injection of 4T1 cells producing a high level of MCP-1 resulted in increased tumor foci in the lung of WT and MCP-1(-/-) mice. Thus, stromal cell-derived MCP-1 in the primary tumors promotes lung metastasis of 4T1 cells, but tumor cell-derived MCP-1 can also contribute once tumor cells enter the circulation. A greater understanding of the source and role of this chemokine may lead to novel strategies for cancer treatment.

DOI： 10.1371/journal.pone.0058791

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Granulomas represent a spectrum of inflammatory sequestration responses that may be initiated by a variety of agents, including non-infectious environmental factors and infectious microbial pathogens. Although this reaction is designed to be protective, the associated tissue injury is often responsible for a profound degree of pathology. While many of the mechanisms that sustain the development of the granuloma are enigmatic, it is accepted that the maintenance of this inflammatory process is dependent upon dynamic interactions between an inciting agent, inflammatory mediators, various immune and inflammatory cells, and structural cells of the involved tissue. The best studied of the host-dependent processes during granuloma development is the innate and adaptive immune response. The innate immune response by antigen-presenting cells [APCs; dendritic cells (DCs) and macrophages] is initiated quickly to protect from overwhelming pathogens, but with time, can also activate the adaptive immune response. APCs, essential regulators of the innate immune response, can respond to microbial ligands through Toll-like receptors (TLRs), which function in the recognition of microbial components and play an important role to link the innate and adaptive immune responses. CD4(+) T helper (Th) cells are essential regulators of adaptive immune responses and inflammatory diseases. Recently, the Notch system has been shown to be an important bridge between APCs and T cell communication circuits. In the present review, we discuss recent findings that explore the mechanisms in the linkage of innate and adaptive immunity, including granulomatous formation though TLRs and Notch activation.

DOI： 10.3389/fimmu.2013.00010

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Bone defects and nonunions are major clinical skeletal problems. Growth factors are commonly used to promote bone regeneration; however, the clinical impact is limited because the factors do not last long at a given site. The introduction of tissue engineering aimed to deter the diffusion of these factors is a promising therapeutic strategy. The purpose of the present study was to evaluate the in vivo osteogenic capability of an engineered bone morphogenetic protein-4 (BMP4) fusion protein. METHODS: BMP4 was fused with a nanosized carrier, collagen-binding domain (CBD), derived from fibronectin. The stability of the CBD-BMP4 fusion protein was examined in vitro and in vivo. Osteogenic effects of CBD-BMP4 were evaluated by computer tomography after intramedullary injection without a collagen-sponge scaffold. Recombinant BMP-4, CBD, or vehicle were used as controls. Expressions of bone-related genes and growth factors were compared among the groups. Osteogenesis induced by CBD-BMP4, BMP4, and CBD was also assessed in a bone-defect model. RESULTS: In vitro, CBD-BMP4 was retained in a collagen gel for at least 7 days while BMP4 alone was released within 3 hours. In vivo, CBD-BMP4 remained at the given site for at least 2 weeks, both with or without a collagen-sponge scaffold, while BMP4 disappeared from the site within 3 days after injection. CBD-BMP4 induced better bone formation than BMP4 did alone, CBD alone, and vehicle after the intramedullary injection into the mouse femur. Bone-related genes and growth factors were expressed at higher levels in CBD-BMP4-treated mice than in all other groups, including BMP4-treated mice. Finally, CBD-BMP4 potentiated more bone formation than did controls, including BMP4 alone, when applied to cranial bone defects without a collagen scaffold. CONCLUSION: Altogether, nanocarrier-CBD enhanced the retention of BMP4 in the bone, thereby promoting augmented osteogenic responses in the absence of a scaffold. These results suggest that CBD-BMP4 may be clinically useful in facilitating bone formation.

DOI： 10.2147/IJN.S44124

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We report a case of 4th metacarpal head collapse of a 19-year-old healthy man. MRI revealed T1 low and T2 high regions in the collapsed 4th metacarpal head, as well as in the right 3rd and left 4th metacarpal head. Our initial diagnosis was occult compression fracture due to avascular necrosis, known as Dieterich's disease. However, pathological findings of surgically resected right 4th metacarpal head were compatible with transient osteoporosis and metacarpal head fracture followed by active tissue repair. The autologous osteochondral transplants from costchondral junction survived and maintained their size and shape even at 10-year follow-up.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

PURPOSE. To elucidate the impact of phacoemulsification on aqueous monocyte chemoattractant protein-1 (MCP-1) levels, and identify its cell origin.
METHODS. For clinical study, aqueous humor samples were collected before and after surgery (17.0 +/- 4.0 months postoperatively) from 21 cataract cases that underwent phacoemulsification and intraocular lens (IOL) implantation. Aqueous MCP-1 levels were determined using a multiplex immunoassay. For animal experiments, rabbits underwent phacoemulsification (+/- IOL). Aqueous humor samples were collected from nonoperated eyes and operated eyes, and immunoassays were performed. Eyes were analyzed by reverse transcription-polymerase chain reaction and immunohistochemical studies.
RESULTS. In the clinical study, mean (+/- SD) aqueous MCP-1 levels were higher postoperatively (1773.5 +/- 321.2 pg/mL) than preoperatively (796.9 +/- 211.3 pg/mL; P &lt; 0.0001). In animal experiments, mean aqueous MCP-1 levels (pg/mL) were higher in postoperative eyes on day 30 (207.1 +/- 62.9) than in nonoperated eyes (31.2 +/- 12.5; P = 0.018). IOL implantation did not affect the changes in MCP-1 levels. After phacoemulsification, MCP-1 mRNA expression was increased in the cornea, iris, ciliary body, and capsular bag. Expression of MCP-1 mRNA in the capsular bag, but not the other tissues, increased from day 30 to 90. Immunohistochemical studies showed positive immunoreactivity for MCP-1 in cells of the posterior capsule after phacoemulsification.
CONCLUSIONS. Aqueous MCP-1 levels were elevated in both human and animal eyes after phacoemulsification. Proliferated lens epithelial cells on the capsule might be the major cell origin for prolonged MCP-1 production after phacoemulsification. (http://www.umin.ac.jp/number, UMIN000005788.) (Invest Ophthalmol Vis Sci. 2012;53:7951-7960) DOI: 10.1167/iovs.12-10231

DOI： 10.1167/iovs.12-10231

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Language：Japanese   Publisher：日本小児感染症学会  

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

MAPKs are involved in acetaminophen (APAP)-hepatotoxicity, but the regulatory mechanism remains unknown. Here, we explored the role of Spred-2 that negatively regulates Ras/ERK pathway in APAP-hepatotoxicity. Spred-2 knockout (KO) mice demonstrated exacerbated liver injury, an event that was associated with increased numbers of CD4(+) T, CD8(+) T and NK cells in the liver compared to the control. Levels of CXCL9/CXCL10 that attract and activate these cells were increased in Spred-2 KO-liver. Kupffer cells isolated from Spred-2 KO mice after APAP challenge expressed higher levels of CXCL9/CXCL10 than those from the control. Upon stimulation with APAP or IFN gamma, naive Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFN gamma and decreased numbers of not only NK cells but also CD4(+) T and CD8(+) T cells in the liver. These results suggest that Spred-2 negatively regulates APAP-hepatotoxicity under the control of Kupffer cells and NK cells. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clim.2012.07.002

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The lung is one of the most immunologically challenged organs and can be affected by a number of pathogens, including bacteria, virus, fungi, and parasites. The development and chronicity of pulmonary infection are determined by the early innate response to the pathogenic stimuli and are regulated at multiple levels. Initial studies have indicated that the interaction of Notch and Notch ligands plays a critical role during development, and further, the Notch system is an important bridge between APCs and T cell communication circuits. APCs are essential regulators of the innate immune response. They can respond to PAMPs through PRRs, which function in the recognition of pathogenic components and play an important role in the innate and adaptive immune response. T cells are essential regulators of adaptive immune responses and infectious diseases. However, the role of the Notch system in the cross-talk between APC and T cells during pulmonary infection is still poorly understood. In the present review, we discuss recent findings that explore the mechanisms underlying the role of Notch signaling in the linkage of innate and adaptive immunity, including pulmonary infection though PPRs and Notch activation.

DOI： 10.1189/jlb.1011529

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background: Pharyngeal cooling decreases brain temperature by cooling carotid arteries. This study was designed to evaluate the principle of pharyngeal cooling in monkeys and humans.
Methods: Monkeys (n = 10) were resuscitated following 12 min of cardiac arrest. Pharyngeal cooling (n = 5), in which cold saline (5 degrees C) was perfused into the cuff at the rate of 500 ml/min, was initiated simultaneously with the onset of resuscitation for 30 min. Patients (n = 3) who were in an intensive care unit were subjected to 30 min of pharyngeal cooling under propofol anesthesia.
Results: In the animal study, core brain temperature was significantly decreased compared with that in the control group by 1.9 degrees C (SD = 0.8, P &lt; 0.001) and 3.1 degrees C (SD = 1.0, P &lt; 0.001) at 10 ruin and 30 min after the onset of cooling, respectively. The cooling effect was more evident in an animal with low postresuscitation blood pressure. Total dose of epinephrine, number of direct current shocks, and recovery of blood pressure were not different between the two groups. The pharyngeal epithelium was microscopically intact on day 5. In the clinical study, insertion of the cuff and start of perfusion did not affect heart rate or blood pressure. Tympanic temperature was decreased by 0.6 +/- 0.1 degrees C/30 min without affecting bladder temperature. The pharynx was macroscopically intact for 3 days.
Conclusions: Pharyngeal cooling rapidly and selectively decreased brain temperature in primates and tympanic temperature in humans and did not have adverse effects on return of spontaneous circulation, even when initiated during cardiac arrest in primates.

DOI： 10.1097/ALN.0b013e3182580536

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Authorship：Last author,　Corresponding author   Language：English   Publisher：AMER ASSOC IMMUNOLOGISTS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS INC  

Acute allograft rejection is one of the significant complications occurring in lung transplant recipients. Early growth response-1 (Egr-1), zinc-finger-type transcription factor, is known as a master switch regulator of diverse chemical mediators. We used an orthotopic mouse model of left lung transplant to elucidate the function of Egr-1 in acute pulmonary rejection.
Left lung grafts retrieved from C57BL/6 wild mice or C57BL/6 Egr-1-null mice were orthotopically transplanted into BALB/c mice; the lungs were harvested at day 1, 3, 5 or 7 after lung transplantation. The grade of acute rejection was histopathologically evaluated. The intragraft gene expression levels of Egr-1 and downstream target mediators were quantitatively measured by real-time polymerase chain reaction. Immunohistochemical analysis was used to determine the location and distribution of the Egr-1 protein in the pulmonary graft.
Severe acute rejection was observed in allografts from wild-type mice at 5 days after transplantation. Only minimal rejection was seen in the lung graft from Egr-1-null donor mice at 5 days after transplantation. Strong upregulation of Egr-1 mRNA transcripts was observed at day 1, which then decreased during the next 5 days. The mRNA of Egr-1 target mediators [interleukin-1-beta (IL-1 beta), monocyte chemotactic protein-1 (MCP-1) and plasminogen activator inhibitor-1] reached maximal levels at day 5. Egr-1-null allografts exhibited significantly lower expressions of IL-1 beta and MCP-1 mRNA (P &lt; 0.05).
Our study showed that deletion of Egr-1 in lung allografts ameliorates severe acute rejection with the reduction of expression levels of chemical mediators, implying a new possible strategy for treating acute pulmonary allograft rejection.

DOI： 10.1093/ejcts/ezr030

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Authorship：Last author,　Corresponding author   Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/j.1440-1827.2011.02741.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

BACKGROUND: Local effects of intra-articular (IA) injection of anti-rabbit tumor necrosis factor alpha monoclonal antibody (anti-TNF alpha mAb) for antigen-induced mono-arthritis (AIA) of the rabbit temporomandibular joint (TMJ) and its systemic influences were evaluated.
METHODS: Biochemical analysis of synovial fluid (SF), clinical and histopathological analyses of TMJ, and serum analysis were performed after inducing AIA in bilateral TMJs of 40 New Zealand White rabbits. IA injection of anti-TNF alpha mAb in unilateral TMJ (TNF blockade side; n = 12) and IgG (n = 12) was performed while saline injected on the contralateral side. TNF alpha and IL-1 beta in SF was analyzed at Days 1, 3, 7, and 21. Joint swelling and head withdrawal reflex threshold (WRT) over TMJs were evaluated in TNF blockade side (n = 12) with histopathological analysis at Days 3, 7, and 21. In remaining four animals with TNF blockade, TNF alpha and anti- TNF alpha mAb in serum were analyzed.
RESULTS: Tumor necrosis factor alpha in SF was significantly lower in TNF blockade side on all days but IL-1 beta was lower only on Day 3. WRT was significantly higher at all times in the blockade side. Less inflammatory reactions and degenerative changes of cartilage were observed on Days 7 and 21 in the blockade side. TNF alpha and anti- TNF alpha mAb were under detection level in serum at all times.
CONCLUSIONS: Intra-articular injection of anti- rabbit TNF alpha mAb in mono-arthritis model was effective to control local inflammation and degenerative joint changes. Further, low-dose IA injection of antibody may not have systemic side effects. J Oral Pathol Med (2012) 41: 96105

DOI： 10.1111/j.1600-0714.2011.01056.x

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

Activated neutrophils and monocytes produce interleukin (IL)-8, a pro-inflammatory chemokine, but also IL-1 receptor antagonist (IL-1ra), which is an anti-inflammatory cytokine. We were interested to see the profiles of IL-8 and IL-1ra in the colonic tissue and in the peripheral blood leukocytes (PBL) during the development of immune complex induced colitis in rabbits. IL-1ra and IL-8 in PBL were measured in 26 rabbits at time 0 h, 24 h, and 48 h after induction of colitis. The colons were removed at 48 h for measuring myeloperoxidase (MPO), ulcer area, IL-1ra and IL-8. Epithelial damage, crypt abscess formation and leukocyte infiltration of the colonic tissue were major features of this colitis model. During the development of colitis, there was an increase in circulating neutrophils and monocytes (P &lt; 0.0001), but not lymphocytes. Likewise, elevated amounts of IL-Ira (P = 0.0001) and IL-8 (P = 0.0219) production by PBL were observed following induction of colitis. Flow cytometry revealed major source of IL-1ra was monocytes, while the main sources of IL-8 were neutrophils and monocytes. There was correlation between MPO and ulcer area (R(s) = 0.6327, P &lt; 0.0001). At 24 h, PBL from MPO(High) group (n = 11) showed increased IL-1ra (P = 0.027) and IL-8 (P = 0.0128) levels vs MPO(Low) group (n = 15). IL-8 production by PBL showed correlation with tissue MPO (R(s) = 0.4273, P = 0.0295). The colitis in this model was associated with an increase in circulating monocytes and neutrophils, which released increased amounts of IL-8 and IL-1ra. Further, IL-8 and IL-1ra showed correlation with the severity of colitis. These observations should significantly further understandings on the role of neutrophils and monocytes in the immunopathogenesis of ulcerative colitis. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.cyto.2011.07.008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Influenza A viral infections have been identified as the etiologic agents for historic pandemics, and contribute to the annual mortality associated with acute viral pneumonia. While both innate and acquired immunity are important in combating influenza virus infection, the mechanism connecting these arms of the immune system remains unknown. Recent data have indicated that the Notch system is an important bridge between antigen-presenting cells (APCs) and T cell communication circuits and plays a central role in driving the immune system to overcome disease. In the present study, we examine the role of Notch signaling during influenza H1N1 virus infection, focusing on APCs. We demonstrate here that macrophages, but not dendritic cells (DCs), increased Notch ligand Delta-like 1 (Dll1) expression following influenza virus challenge. Dll1 expression on macrophages was dependent on retinoic acid-inducible gene-I (RIG-I) induced type-I IFN pathway, and not on the TLR3-TRIF pathway. We also found that IFN alpha-Receptor knockout mice failed to induce Dll1 expression on lung macrophages and had enhanced mortality during influenza virus infection. Our results further showed that specific neutralization of Dll1 during influenza virus challenge induced higher mortality, impaired viral clearance, and decreased levels of IFN-gamma. In addition, we blocked Notch signaling by using gamma-secretase inhibitor (GSI), a Notch signaling inhibitor. Intranasal administration of GSI during influenza infection also led to higher mortality, and higher virus load with excessive inflammation and an impaired production of IFN-gamma in lungs. Moreover, Dll1 expression on macrophages specifically regulates IFN-gamma levels from CD4(+) and CD8(+) T cells, which are important for anti-viral immunity. Together, the results of this study show that Dll1 positively influences the development of anti-viral immunity, and may provide mechanistic approaches for modifying and controlling the immune response against influenza H1N1 virus infection.

DOI： 10.1371/journal.ppat.1002341

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Language：Japanese   Publisher：尾道市立市民病院  

84歳女性。左手指示中手指関節背側の腫脹および発赤、圧痛、左手背部の軽度熱感を主訴に近医を受診後、著者らの施設へ紹介受診となった。左手指示中手指関節背側に対し皮化膿瘍部の穿刺吸引、排膿、ならびに患部切開排膿が施行された。その結果、、微生物的検査では糸状菌が、また培養検査では黒色真菌が検出された。更に加えて生育温度テストではExophiala jeanselmeiが同定された。尚、施行後は抗真菌薬の服用により左手背腫脹は軽減し、疼痛も消失した。

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This paper studied the effects of physiologically available oxidants on HL 60 differentiation induced by all-trans retinoic acid (ATRA) or dimethyl sulfoxide (DMSO). Hydrogen peroxide (15 μM) and taurine chloramine (200 μM) induced HL 60 differentiation, which was detected by CD11b expression and superoxide production. Cd11b and p67phox mRNA expression was also augmented by these oxidants. In contrast, reducing chemicals, such as dithiothreitol, 2,3-dimercapto-1-propanol and N-acetylcysteine inhibited CD11b expression. Notably, DMSO inhibited methionine sulfoxide reductase activity, induced heme oxygenase-1 (ho-1) mRNA and enhanced oxidant-induced cell death, which indicated that DMSO intensified oxidative stress. After the addition of oxidants, ho-1 expression preceded the cd11b expression. Vicinal dithiol-reactive phenylarsine oxide (50 nM) also increased CD11b expression induced by DMSO or ATRA. These observations suggested that oxidative stress enhanced granulocytic differentiation of HL 60 cells and that leukaemic cell differentiation was affected by cellular redox status.

DOI： 10.3109/10715762.2010.503757

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Language：Japanese   Publisher：The Japan Academy of Neurosonology  

We report an 84-year-old woman who underwent carotid artery stenting because of asymptomatic carotid artery stenosis. Perioperative monitoring by three-dimensional ultrasonography (US) revealed more than 80% stenosis in the right carotid artery. The patient initially had transient ischemic attacks manifested by dizziness and vertigo, and was diagnosed by carotid artery US at the brain dock. As intravascular treatment, carotid artery stenting was performed using the Angioguard XP filter protection device and Precise stent. Three-dimensiona] us and three-dimensional reconstruction of color Doppler sonography (CDS) enabled examination of carotid artery blood flow prior to surgery, as well as blood flow in the stent, and conditions of the grafted stent after surgery. Intravascular images, such as plaque shift or subacute thrombosis, were visualized in three spatial dimensions by a combination of three-dimensional US and standard two-dimensional US, indicating their benefit for the evaluation of intra-stent blood flow. On the other hand, two-dimensional US showed better performance in terms of plaque diagnosis, specifically for evaluation of the morphology and properties of plaques, than three-dimensional US. Further improvements in three-dimensional US including CDS systems are anticipated.

DOI： 10.2301/neurosonology.23.13

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Galectin-9 up-regulated Fc gamma RIIb expression of mouse peritoneal macrophages in vitro but down-regulated Fc gamma RIII expression. Galectin-9-treated macrophages stimulated with immune complexes (IC) produced less TNF alpha and IL-1 beta but more IL-10 than PBS-treated macrophages. Macrophage enhancing effects on IC-induced C5a and neutrophil chemotactic activity were also diminished for galectin-9-treated macrophages. In galectin-9-treated mice, the severity of IC-induced arthritis was reduced, as were pro-inflammatory cytokine levels in inflamed joints and serum C5a. Fc gamma RIIb expression of macrophages from galectin-9-treated mice was up-regutated, whereas Fc gamma RIII expression was down-regulated. Macrophages from galectin-9-treated mice produced less TNF alpha and IL-1 beta but more IL-10 than PBS-treated mice. Disease severity of galectin-9-transgenic mice was milder than wild-type mice, whereas that of galectin-9-deficient mice was exaggerated. Furthermore, macrophage Fc gamma RIIb expression in galectin-9-deficient mice was down-regutated, while Fc gamma RIII expression was up-regutated. These results suggest that galectin-9 suppresses IC-induced inflammation partly by regulating Fc gamma R expression on macrophages. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clim.2009.09.004

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

T cells play central rotes in liver diseases, but the regulatory mechanism by cytokine signaling is not well understood. In the present study, we explored the role of SOCS3 in T cells in concanavalin A (ConA)-induced hepatitis. Mice with T-cell-specific overexpression of SOCS3 (SOCS3-cTg) showed reduced hepatic damage and improved mice survival relative to the control, an event that was associated with decreased apoptotic signals Fas and pStat1. Expression of Th1-cytokines/chemokines was decreased in SCCS3-cTg liver with reduced expression of T-bet, a Th1-transcription factor. Flow cytometric analysis of the liver lymphocytes demonstrated that activated CD4(+) T cells, cytotoxic T cells and. natural killer T cells were significantly decreased in SOCS3-cTg liver with decreased expression of perforin and granzyme 8, injurious molecules for hepatocyte damage. These results suggest that forced expression of SOCS3 in T cells prevents ConA-induced liver injury by inhibiting several phases of Th1 responses. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clim.2009.08.015

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BENTHAM SCIENCE PUBL LTD  

Despite availability of successful prevention strategies, HIV continues to spread at alarming rates, especially among women in developing countries. Vaginal microbicides offer a promising approach for blocking transmission of HIV when condom use cannot be negotiated with male partners. A major problem in the development of vaginal microbicides is chemically induced vaginal irritation, which can enhance the risk of HIV transmission. Evaluation of vaginal irritation prior to clinical trials typically uses an expensive and animal-intensive rabbit vaginal irritation model, which could be supplemented by measuring additional inflammatory biomarkers. We studied several immunological parameters as potential biomarkers of vaginal irritation, using the spermicides nonoxynol-9 and benzalkonium chloride as test microbicides. We measured amounts of cytokines, as well as inflammatory cells, in vaginal tissue lysates and on the vaginal surface. We observed that treatment with the selected microbicides increases quantities of the inflammatory cytokines interleukin-1, CXCL8, and CCL2 in the vaginal tissue parenchyma, and of CCL2 on the vaginal surface. This observation was correlated with increases in macrophages in the vaginal parenchyma. We suggest that measurements of CCL2 and macrophages can serve as new inflammatory biomarkers to evaluate the safety of promising novel microbicides for prevention of HIV.

DOI： 10.2174/157016209789973682

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Language：English   Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

DOI： 10.1016/j.micpath.2009.04.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Galectin-9 (Gal-9), a beta-galactoside binding lectin, plays a crucial role in innate and adaptive immunity. in the rat collagen-induced arthritis model, administration of Gal-9 induced repair of existing cartilage injury even when joints were already swollen with cartilage destruction. We thus attempted to explore the role of Gal-9 in chondrocyte differentiation utilizing human mesenchymal stem cell (MSC) pellet Cultures. During chondrogenesis induced by transforming growth factor beta 3 (TGF beta 3), MSCs strongly expressed endogenous Gal-9. Expression of Gal-9 peaked on day 14 and the neutralization of endogenous Gal-9 resulted in the reduced chondrogenesis, indicating possible involvement of Gal-9 in TGF beta-mediated chondrogenesis. In pellets, addition of Gal-9 significantly enhanced TGF beta 3-induced chondrogenesis. as evidenced by increasing proteoglycan content, but not cell proliferation. In the absence of Gal-9, collagen expression by MSCs switched from type I to type II on 28 days after stimulation with TGR beta 3. When MSCs were co-stimulated with Gal-9, the class switch occurred on day 21. In addition, Gal-9 synergistically enhanced TGF beta 3-induced phosphorylation of Smad2, though Gal-9 did not itself induce detectable Smad2 phosphorylation. These results Suggest that Gal-9 has a beneficial effect on cartilage repair in injured joints by induction of differentiation of MSCs into chondrocytes. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bone.2009.01.365

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Betamethasone sodium phosphate (BSP) is usually used as a steroid therapy for human brain edema. High doses of BSP (36 mg/kg) twice a day for two days statistically reduced the mortality rate and improved the survival period of Stx2 (1.4 mu g/kg: 1.6LD(50))-toxemic rabbits. We made evaluations on three kinds of magnetic resonance images (MRI) including T1-weighted, T2-weighted, and enhanced MRI using gadopentetate dimeglumine (Gd-DTPA) to detect brain lesion induced by an intravenous injection of Stx2 in rabbits. Enhanced T1-weighted MRI was the most sensitive tool to find leakage of Gd-DTPA suggesting impairment of the blood brain barrier caused by Stx2. Enhanced MRI revealed that BSP treatment inhibited the leakage of Gd-DTPA, as directly evidenced by the protective effect of BSP against brain edema induced by intravenous injection of Stx2. Interleukin 1 beta was not induced after Stx2 treatment in brain primary mixed cell culture. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.micpath.2009.01.005

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Leukemic cell apoptosis may be enhanced by appropriate oxidative stress. We report here the mechanism of Jurkat cell apoptosis by monochloramine (NH(2)Cl), a neutrophil-derived oxidant. NH(2)Cl induced caspase-dependent apoptosis, which was preceded by cytochrome c and Smac/Diablo release from mitochondfia. Within 10 min of NH(2)Cl treatment, c-Jun N-terminal kinase (JNK) activation and elevation of cytosolic Ca(2+) were observed. JNK inhibitors (SP600125 or JNK inhibitor VIII) significantly suppressed the apoptosis as well as caspase cleavage and cytochrome c release. In contrast, Ca(2+) chelation by EGTA + acetoxymethyl-EGTA had no effects on apoptosis. Our results indicated that JNK activation contributed most importantly to the NH(2)Cl-induced apoptosis. (C) 2008 Elsevier Ltd. All fights reserved.

DOI： 10.1016/j.leukres.2008.07.009

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Despite advances in the development of powerful antibiotics and intensive care unit, sepsis is still life threatening and the mortality rate remains unchanged for the past three decades. Recent prospective trials with biological response modifiers have shown a modest clinical benefit. The pathological basis of sepsis is initially an excessive inflammatory response against invading pathogens, leading to systemic inflammatory response syndrome (SIRS). Evidence reveals that a variety of inflammatory mediators orchestrate the intense inflammation through complicated cellular interactions. More recent data indicate that most septic patients survive this stage and then subjected to an immunoparalysis phase, termed compensatory anti-inflammatory response syndrome (CARS), which is more fatal than the initial phase. Sepsis is a complicated clinical syndrome with multiple physiologic and immunologic abnormalities. In this review, we summarize the recent understandings of the pathophysiology of sepsis, and introduce recent patents on diagnosis, treatment and prophylaxis for sepsis. © 2009 Bentham Science Publishers Ltd.

DOI： 10.2174/187221309787158416

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

To clarify the mechanism of coronary outward remodeling, we examined atherosclerotic coronary arteries morphologically using WHHLMI rabbits that develop coronary atherosclerosis spontaneously. Perfusion-fixed coronary segments of WHHLMI rabbits were prepared at 500 mu m intervals. After immunohistochemical staining and histopathological staining, the areas and lengths of the arterial wall and the lesions were measured. Obvious outward remodeling was observed in coronary sections with greater than 40% cross-sectional narrowing. In coronary sections with greater than 40% cross-sectional narrowing, the tunica media was thick at the shoulder of atheromatous plaque and was thin beneath the atheromatous plaques. Macrophages infiltrated those attenuated tunica media expressed matrix metalloproteinases and oxidized LDL was accumulated in those areas. In those areas, collagen fibers and the internal elastic lamina had disappeared partly and apoptotic smooth muscle cells were observed. Proliferation of smooth muscle cells was observed at the attenuated tunica media and adjacent adventitia. The present results suggest that invasion of atheromatous plaques into the tunica media causes coronary outward remodeling. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.atherosclerosis.2008.02.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The effects of galectin-9 on a mouse collagen-induced arthritis (CIA) model were assessed to clarify whether galectin-9 suppresses CIA by regulating T cell. immune responses. Galectin-9 suppressed CIA in a dose-dependent manner, and such suppression was observed even when treatment was started on 7 days after the booster, indicating its preventive and therapeutic effects. Galectin-9 induced the decreased levels of pro-inflammatory cytokines, IL-17, IL-12, and IFN gamma in the joint. Gatectin-9 induced the decreased number of CD4(+) TIM-3(+) T cells in peripheral blood. Galectin-9-deficient mice became susceptible to CIA may be by increased number of CD4(+) TIM-3(+) T cells and decreased number of Treg cells. We further found that galectin-9 induces differentiation of naive T cells to Treg cells, and it suppresses differentiation to Th17 cells in vitro. The present results suggested that galectin-9 ameliorates CIA by suppressing the generation of Th17, promoting the induction of regulatory T cells. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clim.2008.01.006

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Language：Japanese   Publisher：岡山県臨床細胞学会  

32歳女。主訴は左乳房のしこりであった。腫瘤は20cm大で、針生検にて血管系腫瘍が疑われた。右乳房にも超音波・MRIで左腫瘍と類似した腫瘤影があり、左皮下乳腺全摘+右乳腺部分切除術を施行した。摘出材料は出血を伴った充実性腫瘤で、HE標本ではクロマチン増量と核異型を有する短紡錘形細胞が毛細血管類似の管腔を形成し、浸潤性増殖していた。捺印細胞標本では赤血球を背景に単在〜集塊状に類円形細胞と紡錘形細胞が混在する腫瘍細胞を認め、いずれも切れ込みを有する核や核の抱きこみ像を多数認めた。細胞質内にはhaloを伴う赤血球様物質を容れた腫瘍細胞やベルリン青陽性ヘモジデリン顆粒を貪食した細胞を認め、免疫染色ではCD31・CD34が類円形細胞・紡錘形細胞ともに陽性で、MIB1陽性率は40%であり、血管肉腫と診断した。

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Language：Japanese   Publisher：(一社)日本病理学会  

症例は59歳女性。左膝窩部の皮膚から皮下組織におよぶ8×6cm大の腫瘍が存在し、腫瘍切除術が施行された。組織学的には、通常型の隆起性皮膚線維肉腫(dermatofibrosarcoma protuberans;DFSP)の領域から移行して明瞭なnuclear palisadingを示す部分が散在性に認められた。いずれの領域もCD34はびまん性に強陽性を示した。また線維肉腫に相当する高悪性度肉腫の領域が存在し、その部分ではCD34が減弱〜陰性化していた。Nuclear palisadingを示すDFSPから発生した稀なfibrosarcomaの1例を報告する。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2008&ichushi_jid=J03623&link_issn=&doc_id=20080515230004&doc_link_id=%2Fcd9jjodp%2F2008%2F002502%2F004%2F0072-0076%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcd9jjodp%2F2008%2F002502%2F004%2F0072-0076%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：Japan Heart Foundation  

DOI： 10.11281/shinzo1969.40.10_875

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Language：Japanese   Publisher：日本医学教育学会  

記事種別: 特集 ; 会議・学会報告・シンポジウム

DOI： 10.11307/mededjapan1970.39.205

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Language：Japanese   Publisher：岡山県臨床細胞学会  

70歳女。5年前に右乳癌にて乳房切除を施行され化学療法を続けてきたが、CEAの上昇とともに結腸の多発通過障害が出現したため開腹手術を行った。腹膜・大網に播種結節を認め、貯留腹水の細胞診では核異型が軽度で散在性ないし小集塊状の腫瘍細胞が散見された。一部の腫瘍細胞では細胞質の突出像や相互封入像を認め、PAS反応は細胞質にびまん性陽性を認めた。大網生検組織でも均一な小型の異型細胞が疎な結合を示して浸潤性に増殖し、原発巣に類似する組織所見を認めた。PAS反応では腫瘍細胞の胞体にびまん性陽性を認め、免疫染色ではエストロゲン受容体陽性、プロゲステロン受容体・HER2・Eカドヘリン陰性であり、乳癌invasive lobular carcinoma転移と診断した。

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Authorship：Lead author,　Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

The innate immune system provides immediate defense against infection and serves as the first line of host defense during infection. In innate immunity, leukocytes such as neutrophils; and macrophages recognize and respond to pathogens in a non-specific manner. Therefore, the recruitment and activation of leukocytes are essential in innate immunity, and are governed by a variety of chemical mediators including cytokines. Cytokines are generally divided into 2 types, termed type-1 and type-2 cytokines. Type-1 cytokines are important in local host defense, while type-2 cytokines play a protective role when inflammatory response spreads to the body. These cytokines exert their biological functions through the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. STAT1/3/4/6 are transcription factors that mediate IFN gamma/IL-10/IL-12/IL-13 cytokine signaling, respectively. Evidence indicates that STAT proteins have a significant impact on innate immunity during sepsis. This review focuses on recent understandings in the regulation of innate immunity by STAT proteins during sepsis and septic shock. The suppressor of cytokine signaling (SOCS) proteins are a family of SH2 domain-containing cytoplasmic proteins that complete a negative feedback loop to attenuate signal transduction from cytokines that act through the JAK/STAT pathway. The participation of SOCS proteins in sepsis is also discussed.

DOI： 10.18926/AMO/32897

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Language：English   Publisher：ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD  

DOI： 10.1016/j.cyto.2007.07.009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Peritoneal adhesions are a significant complication of surgery and visceral inflammation; however, the mechanism has not been fully elucidated. The aim of this study was to clarify the mechanism of peritoneal adhesions by focusing on the cell trafficking and immune system in the peritoneal cavity. We investigated the specific recruitment of peritoneal macrophages (PM phi) and their expression of chemokine receptors in murine models of postoperative and postinflammatory peritoneal adhesions. PM phi aggregated at the site of injured peritoneum in these murine models of peritoneal adhesions. The chemokine receptor CCR8 was up-regulated in the aggregating PN phi when compared with naive PM phi. The up-regulation of CCR8 was also observed in PM phi, but not in bone marrow-derived M phi, treated with inflammatory stimulants including bacterial components and cytokines. Importantly, CCL1, the ligand for CCR8, a product of both PM phi and peritoneal mesothelial cells (PMCs) following inflammatory stimulation, was a potent enhancer of CCR8 expression. Cell aggregation involving PM phi and PMCs was induced in vitro in the presence of CCL1. CCL1 also up-regulated mRNA levels of plasminogen activator inhibitor-1 in both PM phi and PMCs. CCR8 gene-deficient mice or mice treated with anti-CCL1-neutralizing Ab exhibited significantly reduced postoperational peritoneal-adhesion. Our study now establishes a unique autocrine activation system in PM phi and the mechanism for recruitment of PM phi together with PMCs via CCL1/CCR8, as immune responses of peritoneal cavity, which triggers peritoneal adhesions.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

A 24-year-old woman was found dead in her bed. There had been an episode of fainting with cervicodynia 1 day before death but no significant past medical history, except for menstrual irregularities. Post-mortem examination revealed that death was due to hemopericardium caused by rupture of the ascending aorta by thoracic aortic dissection (Stanford type A). Microscopically, weakness of the aorta was due to cystic medial necrosis. On external examination, short stature, a short neck and multiple pigmented nevi were observed, while internal examination revealed coarctation of the aorta and funicular ovaries. Examination of the X chromatin showed a decrease in numbers of Barr bodies in the tissues, and a 45,X/46,XX mosaicism was suspected. It is concluded that the cause of death was aortic dissection due to Turner's syndrome.

DOI： 10.1111/j.1440-1827.2007.02084.x

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Cytokines have been implicated in the progression of acetaminophen (APAP)-induced acute liver injury. Suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling by inhibiting the JAK-STAT pathway, but their role in APAP hepatotoxicity is unknown. In this present study, we attempted to explore the role of SOCS3 in T cells in APAP-induced liver injury. Mice with a cell-specific overexpression of SOCS3 in T cells (SOCS3Tg, in which Tg is transgenic) exhibited exaggerated hepatic injury after APAP challenge, as evidenced by increased serum alanine aminotransferase levels, augmented hepatic necrosis, and decreased survival relative to the wild-type mice. Adaptive transfer of SOCS3Tg-CD4(+) T cells into T and B cell-deficient RAG-2(-/-) mice resulted in an exacerbated liver injury relative to the control. In SOCS3Tg mice, hepatocyte apoptosis was enhanced with decreased expression of antiapoptotic protein bcl-2, whereas hepatocyte proliferation was reduced with altered cell cycle-regulatory proteins. Levels of IFN-gamma and TNF-alpha in the circulation were augmented in SOCS3Tg mice relative to the control. Studies using neutralizing Abs indicated that elevated IFN-gamma and TNF-alpha were responsible for the exacerbated hepatotoxicity in SOCS3Tg mice. Activation of STATl that is harmful in liver injury was augmented in SOCS3Tg hepatocytes. Alternatively, hepatoprotective STAT3 activation was decreased in SOCS3Tg hepatocytes, an event that was associated with augmented SOCS3 expression in the hepatocytes. Altogether, these results suggest that forced expression of SOCS3 in T cells is deleterious in APAP hepatotoxicity by increasing STAT1 activation while decreasing STAT3 activation in hepatocytes, possibly through elevated IFN-gamma and TNF-alpha.

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Language：Japanese   Publisher：(一社)日本病理学会  

非定型奇形腫様/ラブドイド腫瘍(atypical teratoid/rhabdoid tumor(AT/RT))はrhabdoid cellの出現を特徴とした中枢神経に発生する胎児性腫瘍で予後はきわめて不良である。症例は生後6ヵ月、女児。頭囲の拡大、発達遅延を認め、近医にて水頭症を指摘された。腫瘍は松果体部、中脳被蓋部、第四脳室にかけて存在し、脊髄に播種性病変が存在した。組織学的に腫瘍はprimitive neuroectodermal tumor(PNET)様の小型未熟細胞の充実性増殖が主体をなし、小範囲にrhabdoid cellや索状配列を示す領域が存在した。AT/RTと診断し、腫瘍摘出後化学療法が施行されたが、5ヵ月後水頭症が悪化し死亡した。(著者抄録)

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling by inhibiting the JAK-STAT signal transduction pathway, but their role in innate immunity remains to be investigated. In the present study, we demonstrate that overexpression of SOCS5 in T cells augments innate immunity during septic peritonitis induced by cecal ligation and puncture (CLP). Mice with a cell-specific overexpression of SOCS5 in T cells (SOCS5 transgenic (Tg)) were resistant to the lethality relative to the wild-type (WT) mice. This was most likely due to the enhanced innate immunity in SOCS5Tg mice, as bacterial burden in SOCS5Tg mice was significantly lower than WT mice. Accumulation of neutrophils and macrophages was augmented in SOCS5Tg mice, an event that was accompanied by increased peritoneal levels of IL-12, IFN-gamma, and TNF-alpha. In vitro bactericidal activities of macrophages and neutrophils were enhanced in SOCS5Tg mice. Both neutrophils and macrophages from WT mice adopted enhanced bacterial killing activity when cocultured with CD4(+) T cells from SOCS5Tg mice, relative to CD4(+) T cells from WT mice. Adoptive transfer of SOCS5Tg-CD4(+) T cells into T- and B cell-deficient RAG-2(-/-) mice resulted in augmented leukocyte infiltration and increased peritoneal levels of IL-12, IFN-gamma, and TNF-alpha after CLP, as compared with the controls. Furthermore, CLP-induced bacterial burden in RAG2(-/-) mice harboring SOCS5Tg-CD4(+) T cells was significantly reduced relative to the controls. These findings provide evidence that intervention of SOCS5 expression in T cells affects innate immunity, which highlight a novel role of T cells during sepsis.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Neuromedin U (NMU) is a neuropeptide involved in appetite, circadian rhythm, and pronociception. However, the NMU receptor NMU-R1 has been shown to be expressed in immune cells and NMU promotes mast cell-dependent inflammation. In this study, we demonstrated that NMU plays an important role in IL-6 production in macrophages. NMU-deficient mice were resistant against cecal ligation puncture- as well as LPS-induced septic shock. IL-6 but not TNF-alpha levels were markedly reduced in LPS-treated NMU-deficient mice compared with wild type mice. Both NMU and NMU-R1 were expressed in wild type peritoneal macrophages, and treatment with LPS resulted in up-regulation of NMU but down-regulation of NMU-RI expression, however, no down-regulation of NMU-RI was observed in NMU-deficient macrophages where LPS-induced IL-6 production was severely reduced. These data suggest that LPS-induced IL-6 expression is partly dependent on autocrine/paracrine activation of the NMU-NMU-R1 signals in macrophages. (c) 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2006.01.075

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

BACKGROUND: Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) staining is a widely accepted method for the detection of DNA fragmentation in nuclei of apoptotic cells. Tumor necrosis factor (TNF)-alpha is closely associated with changes in condylar cartilage and modulates apoptosis in various tissues including cartilage. The aim of this study was to investigate the relationship between apoptotic chondrocytes and TNF-alpha in a rabbit model of arthritis.
METHOD: Unilateral temporomandibular joint (TMJ) arthritis was induced in 20 adult New Zealand White rabbits. From 1 day to 6 weeks after the induction of arthritis, immunohistochemical analysis for TNF-alpha and TUNEL was performed.
RESULTS: In condylar cartilage, TNF-alpha-positive cells and TUNEL-positive cells were localized together. TNF-alpha-positive chondrocytes seemed to precede TUNEL-positive cells.
CONCLUSIONS: The results of the present study suggest that TNF-alpha may be involved in apoptosis and/or apoptotic necrosis of chondrocytes as TMJ arthritis progresses from the acute to chronic stage.

DOI： 10.1111/j.1600-0714.2006.00367.x

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：FEDERATION AMER SOC EXP BIOL  

An effective clearance of microbes is crucial in host defense during infection. In the present study, we demonstrate that CC chemokine receptor 8 (CCR8) skews innate immune response during septic peritonitis induced by cecal ligation and puncture (CLP). CCR8 was expressed in resident peritoneal macrophages and elicited leukocytes during CLP in the wild-type CCR8+/+ mice. CCR8-/- mice were resistant to CLP-induced lethality relative to CCR8+/+ mice, and this resistance was associated with an augmented bacterial clearance in CCR8-/- mice. In vitro, peritoneal macrophages from CCR8-/- mice, but not neutrophils, exhibited enhanced bactericidal activities relative to those from CCR8+/+ mice. Upon stimulation with the bacterial component LPS, elevated levels of superoxide generation, lysosomal enzyme release, and nitric oxide generation, effector molecules for bacterial killing were detected in CCR8-/- macrophages relative to CCR8+/+ macrophages. In addition, CCR8-/- macrophages produced significantly higher levels than CCR8+/+ macrophages of several cytokines and chemokines known to augment bactericidal activities of leukocytes that include TNF-alpha, IL-12, macrophage-derived chemokine (MDC/CCL22), macrophage inflammatory protein (MIP)-2, and KC. Altogether, these results indicate that CCR8 may have a negative impact on host defense during septic peritonitis, providing a new paradigm for the role of CCR8 in innate immunity.

DOI： 10.1096/fj.04-1728fje

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The potential use of hydrophilic cycloclextrins (CyDs) as an inhibitor for lipopolysaccharide (LPS) was examined. Of the five CyDs used in this study, dimethylacetyl-beta-cyclodextrin (DMA7-beta-CyD) had greater inhibitory activity than other CyDs against the production of nitric oxide (NO) and various proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) in murine macrophages stimulated with two serotypes of LPS and lipid A. The inhibitory effect of DMA7-beta-CyD on NO production was also observed in macrophages stimulated with lipoteichoic acid (LTA), but not peptidoglycan (PGN), polyinosinic-polycytidylic acid (poly I:C) or CpG oligonucleotide (CpG-ODN). Several studies have suggested that the inhibitory effects of DMA7-beta-CyD could be ascribed to the interaction with LPS. Simultaneous administration of DMA7-beta-CyD not only intraperitoneally but also intravenously and intraperitoneal injection of aqueous solution containing LPS and D-galactosamine in murine endotoxin shock model suppressed fatality. Also, DMA7-beta-CyD decreased blood level of TNF-alpha as well as serum levels of aspartate transaminase (AST) and alanine transaminase (ALT) in mice. In conclusion, DMA7-beta-CyD may have promise as a new therapeutic agent for endotoxin shock induced by LPS. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bcp.2005.08.021

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Objectives/Hypothesis. To evaluate the effects of denervation on muscle fibers and neuromuscular junctions (NMJ) of the rat thyroarytenoid (TA) muscle with a histochemical method to monitor the status of degenerative NMJ. Study Design: Quantitative assessment to monitor the status of degenerative muscle fibers and NMJ in the TA muscle. Methods: Wistar rats were killed at 6, 12, 18, and 24 hours and at 2, 4, and 10 weeks after left recurrent laryngeal nerve (RLN) transection. Hematoxylin-eosin stain was used to evaluate the atrophic changes of the TA muscle. The pre- and postsynaptic structures of the NMJ were detected histochemically. These changes were evaluated by comparing the results between the treated (T) and untreated (U) sides (T/U ratio) in the same section. Results. The atrophic changes in the TA muscle progressed gradually, and at 10 weeks, the T/U ratios of the entire muscle area and of the muscle fiber size decreased to 53.2 +/- 10.7% and 55.5 +/- 6.8%, respectively (P &lt; .01). The number of nerve terminals decreased significantly at 18 hours (P &lt; .01), and they disappeared completely by 24 hours. In contrast, at 10 weeks, 70.5 +/- 12.4% (P &lt; .01) of acetylcholine receptors (AchRs) were preserved. Conclusions: In the rat TA muscle, denervation. influences the presynaptic nerve terminals more than the postsynaptic AchRs and the muscle fibers. The results could be a basis for understanding the mechanism of laryngeal denervation and reinnervation processes in animal models.

DOI： 10.1097/01.mlg.0000177076.33294.89

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Inflammation is counterbalanced by anti-inflammatory cytokines such as IL-10, in which Stat3 mediates the signaling pathway. In this study, we demonstrate that resident macrophages, but not other cell types, are important targets of IL-10 in a murine model of acute peritonitis. Injection of thioglycollate i.p. induced a considerable number of neutrophils and macrophages in the peritoneum, which was significantly augmented in mice with a cell-type specific disruption of the Stat3 gene in macrophages and neutrophils (LysMcre/Stat3flox(/-) mice). The augmented leukocyte infiltration was accompanied by increased peritoneal levels of TNF-alpha, MIP-2, KC chemokine (KC), and MCP-1/CCL2. Stat3 was tyrosine phosphorylated in peritoneal resident macrophages as well as infiltrating leukocytes in the littermate controls, suggesting that Stat3 in either or both of these cells might play a regulatory role in inflammation. The peritoneal levels of TNF-alpha, MIP-2, KC, and MCP-1 were similarly elevated in LysMcre/Stat3(flox/)-mice rendered leukopenic by cyclophosphamide treatment as compared with the controls. Adoptive transfer of resident macrophages from LysMcre/Stat3(flox/-) mice into the control littermates resulted in increases in the peritoneal level of TNF-alpha, MIP-2, KC, and MCP-1 after i.p. injection of thioglycollate. Under these conditions, control littermates harboring LysMcre/Stat3(flox/-) macrophages exhibited an augmented leukocyte infiltration relative to those received control macrophages. Taken together, these data provide evidence that resident macrophages, but not other cell types, play a regulatory role in inflammation through a Stat3 signaling pathway. Stat3 in resident macrophages appears to function as a repressor protein in this model of acute inflammation.

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Language：Japanese   Publisher：西日本整形・災害外科学会  

58歳男.近医にて1年前に右手掌軟部腫瘤に対して摘出術が施行され,4ヵ月前に局所再発に対して再度摘出術が施行され,平滑筋肉腫である腱鞘巨細胞腫と診断された.今回,再び局所に腫瘤が出現したため紹介来院となった.臨床経過・局所所見・MRI所見などより腱鞘巨細胞腫と診断し摘出術を施行した.摘出標本の病理組織学的所見と平滑筋肉腫との鑑別目的の免疫染色結果から悪性腱鞘巨細胞腫と診断された.CTによる全身検索にて肺野に多発性結節性病変を認め,肺転移と診断し化学療法を開始した.悪性腱鞘巨細胞腫と平滑筋肉腫の鑑別には免疫組織化学的検索が有用であった.手に悪性腫瘍が発生することは比較的稀であるが,術前の良性・悪性の鑑別は慎重に行うべきであるものと考えられた

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Study Design. A new hernia model that simulates human disc herniations was developed in rabbits. The herniated discs were examined by gross appearance and histology and production of tumor necrosis factor alpha, interleukin-1beta, and monocyte chemoattractant protein-1 was investigated.
Objectives. To clarify the early mechanism of spontaneous herniated disc resorption.
Summary of Background Data. Macrophage infiltration in herniated discs is essential for disc resorption. However, surgically removed human herniated disc tissues and existing animal hernia models are not suitable for analyzing the mechanism of macrophage infiltration. Recently, we have demonstrated that intervertebral disc cells are capable of producing monocyte chemoattractant protein-1, a potent macrophage chemoattractant, after stimulation with tumor necrosis factor alpha and interleukin-1beta.
Methods. Intervertebral disc herniations were surgically developed in rabbits using a new technique. The herniated discs were excised at appropriate time intervals after the surgery, and the size and histologic findings were examined. Expressions of tumor necrosis factor alpha, interleukin-1beta, and monocyte chemoattractant protein-1 in herniated discs were investigated immunohistochemically.
Results. A new rabbit model of disc herniation was established. The herniated discs spontaneously reduced in size by 12 weeks postsurgery. Infiltrating cells, mainly composed of macrophages, were observed from day 3. Immunohistochemically, intervertebral disc cells in the herniated discs produced tumor necrosis factor alpha and interleukin-1beta on day 1, followed by monocyte chemoattractant protein-1 on day 3.
Conclusions. The new hernia model appears to be very useful for studying herniated disc resorption. Intervertebral disc cells may produce inflammatory cytokines/chemokine immediately after the onset of disc herniation, possibly triggering subsequent macrophage infiltration that leads to disc resorption.

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：URBAN & FISCHER VERLAG  

A case of an unusual variant of fundic gland polyp (FGP) composed of chief cell hyperplasia with structural and nuclear atypia in an 87-year-old woman is presented. Gastrointestinal endoscopy revealed a sessile polyp in the cardia/corpus transition zone and a polypoid lesion in the fundus. Histologically, the polyp in the cardia/corpus showed a typical appearance of FGP, while that in fundus demonstrated a tumorous lesion composed of irregular branched tubules with nuclear stratification. Despite the structural distortion and nuclear atypia, mitotic figures were absent and MIB-1 positive cells were less than 3%. Immunohistochemically, the cytoplasms of the tubules were negative for gastric mucin and Muc-5AC glycoprotein, but mostly positive for pepsinogen-I, indicating that the proliferated glands consisted mainly of chief cells, not mucous cells. Parietal cells were occasionally found in the glands. At the periphery of the lesion, microcysts composed of parietal cells, chief cells, and mucous cells had developed. Altogether, the polyp in the fundus was diagnosed as an unusual variant of FGP with chief cell hyperplasia. This FGP should be differentiated from tubular adenocarcinoma. Proliferation of chief cells with occasional parietal cells is critical for the differential diagnosis. (c) 2004 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2004.10.005

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

C57BL/6 and BALB/c mice are prototypical Th1- and Th2-type mouse strains, respectively. In the present study, we attempted to characterize the innate immune response of macrophages from these mouse strains. Macrophages from C57BL/6 mice produced higher levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12 than those from BALB/c mice after stimulation with macrophage-activating lipopeptide-2 (MALP-2, a synthetic TLR-2 ligand) or lipopolysaccharide (LPS, a TLR-4 ligand). The augmented IL-12 production by C57BL/6 macrophages increased interferon-gamma and, in contrast, decreased IL-13 production by CD4+ T cells. On stimulation with MALP-2 or LIPS, C57BL/6 macrophages produced lysosomal enzyme and nitric oxide, effector molecules for bacterial killing, whereas BALB/c macrophages did not. Bactericidal activity of BALB/c macrophages was impaired relative to C57BL/6 macrophages when cells were infected with live bacteria in vitro. In a murine model of septic peritonitis induced by cecal ligation and puncture (CLP), BALB/c mice failed to facilitate bacterial clearance relative to C57BL/6 mice despite an augmented peritoneal leukocyte infiltration that was associated with increased peritoneal levels of cytokines/chemokines. BALB/c mice exhibited increased plasma and hepatic levels of cytokines/chemokines, resulting in an exaggerated systemic inflammation as determined by acute-phase proteins. Finally, BALB/c mice were vulnerable to CILP-induced lethality relative to C57BL/6 mice. Altogether, innate immune response of macrophages is different between these mouse strains, which may affect the development of Th1 and Th2 adaptive immunity in these strains. Reduced systemic inflammatory response in C57BL/6 mice that may result from an eminent local response appears to be beneficial during sepsis.

DOI： 10.1097/01.shk.0000142249.08135.e9

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：CARFAX PUBLISHING  

THE aim of this study was to determine the role of CC chemokine CCL6/C10 in acute inflammation. Intraperitoneal injection of thioglycollate increased peritoneal CCL6, which peaked at 4 h and remained elevated at 48 h. Neutralization of CCL6 significantly inhibited the macrophage infiltration (34-48% reduction), but not other cell types, without decreasing the other CC chemokines known to attract monocytes/macrophages. CCL6 was expressed in peripheral eosinophils and elicited macrophages, but not in elicited neutrophils. Peritoneal CCL6 level was not decreased in granulocyte-depleted mice where eosinophil influx was significantly impaired. Thus, CCL6 appears to contribute to the macrophage infiltration that is independent of other CC chemokines. Eosinophils pre-store CCL6, but do not release CCL6 in the peritoneum in this model of inflammation.

DOI： 10.1080/09629350400014172

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC  

Controversy persists pertaining to the role of CCR4 ligands, namely CCL17 (or thymus and activation regulated chemokine; TARC) and CCL22 (or macrophage-derived chemokine; MDC), in Th2-type cytokine-dominated responses in the lung. Accordingly, the present study addressed the relative role of each of these CC chemokines during an evolving pulmonary granulomatous response elicited by the intrapulmonary embolization of live Schistosoma mansoni eggs into S. mansoni-sensitized mice. CCL22 protein expression peaked at day 4, but CCL17 levels were not increased significantly at any time after egg challenge. CCR4 transcript and protein expression were highest at day 8 after egg embolization and CCR4 protein was prominently expressed in macrophages surrounding S. mansoni eggs. Systemic immunoneutralization of CCL22 from the time of egg injection into S. mansoni-sensitized mice for 8 days significantly decreased CCR4 protein expression, the eosinophil content, the overall size of the egg granuloma, and its hydroxyproline content. Whole lung levels of interferon-gamma were also significantly increased at day 8 in anti-CCL22-treated mice. The systemic immunoneutralization of CCL17 had a lesser effect on all of the granuloma parameters listed above, but this antibody treatment significantly decreased granuloma hydroxyproline content to a greater extent than the anti-CCL22 antibody treatment. In addition, the immunoneutralization of CCL17 significantly increased whole lung levels of interleukin (IL)-4, IL-5, IL-13, transforming growth factor-beta, ILL-12, and tumor necrosis factor-a at day 8 after egg infusion. Thus, these studies demonstrate a major role for CCL22 and a lesser role for CCL17 during an evolving S. mansoni egg granuloma in the lung.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY, INC  

Objective: Pro-inflammatory cytokine-driven mechanisms have been implicated in vein graft failure, though little is known about the effect of hemodynamic factors and anti-inflammatory counter-regulatory mechanisms. We hypothesized that early temporal expression of the pro-inflammatory cytokine interleukin (IL)-1beta and the anti-inflammatory cytokine IL-10 proceeds by way of wall shear stress-dependent pathways in the arterializing vein graft.
Methods. Rabbits (n = 27) underwent bilateral jugular vein carotid interposition grafts, and simultaneous unilateral distal carotid branch ligation, to produce both low-flow and high-flow grafts in the same animal. Vein grafts were harvested at 1, 3, 7, 14, and 28 days and were assessed for architecture, wall shear stress, and cytokine messenger RNA levels (quantitative real-time two-step reverse transcription polymerase chain reaction).
Results. The model resulted in an immediate 90% flow reduction (P &lt; .001, paired t test) in the vein graft on the ligated side, and a 36% increase (P = .01) in contralateral graft flow. This persisted as similar to15-fold flow differential throughout the 28-day period. The construction yielded a 15-fold differential in wall shear stress between low-flow and high-flow vein grafts (P &lt; .001, two-way repeated measures analysis of variance). Intimal hyperplasia began by day 3, and was 6-fold more in low wall shear grafts by 28 days (230.6 +/- 35.4 mum intimal thickness vs 36.1 +/- 17.6 mum for low shear versus high shear grafts; P = .001). For both cytokines time independently affected mRNA expression (P &lt; .001, global analysis of variance). Exposure of vein grafts to the arterial circulation markedly up-regulated IL-10 at 1 day, with significantly more induction in the low shear setting (P =.002). IL-1beta protein localized to the developing neointima at days 1 and 3. Conversely, IL-10 slowly increased until day 14, with significantly more expression in the high shear grafts (P &lt; .001).
Conclusions. Vein graft adaptation induces early pro-inflammatory cytokine IL-1beta expression and delayed protective IL-10 expression (most notable under high shear conditions), both of which are modulated by wall shear. These differential temporal windows offer strategies for appropriately timed pro-inflammatory or anti-inflammatory therapies to interrupt pathologic vein graft adaptations. (J Vasc Surg 2004;40:345-50.)
Clinical Relevance: Neointimal hyperplasia continues to limit the durability of vein bypass grafts. Emerging evidence suggests that inflammatory mechanisms drive the neointimal hyperplasic response. This study demonstrates that specific hemodynamic forces (altered wall shear stress) differentially affect early pro-inflammatory interleukin (IL)-1beta and delayed anti-inflammatory IL-10 signaling. These distinct temporal windows for IL-1beta and IL-10 cytokine expression offer strategies for appropriately timed pro-inflammatory and anti-inflammatory therapies to interrupt pathologic vein graft adaptations.

DOI： 10.1016/j.jvs.2004.03.048

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OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory condition characterized by a cellular influx and destruction of the joint architecture. Chemokines characteristically regulate leukocyte recruitment and activation. Chemokine (CC motif) receptor-like 2 (CCRL2) is an orphan receptor with homology to other CC chemokine receptors. We undertook this study to examine CCRL2 expression in RA, cytokine regulation of expression, and the source of a putative ligand in an attempt to determine the role of this receptor during inflammation. METHODS: Expression of CCRL2 on joint-infiltrating leukocytes was examined by immunocytochemistry. In vitro studies evaluated CCRL2 expression in primary neutrophils using Northern and Western blotting and reverse transcriptase-polymerase chain reaction. HEK 293 cells expressing two splice variants of CCRL2 (HEK/CCRL2A or HEK/CCRL2B) were generated with a retroviral expression system, and their migration in response to fractions of synovial fluid (SF) from RA patients was examined using a 48-well chamber. RESULTS: CCRL2 expression was observed on all infiltrating neutrophils and on some macrophages obtained from the SF of 5 RA patients. In vitro studies of primary neutrophils revealed that CCRL2 messenger RNA (mRNA) was rapidly up-regulated following stimulation with lipopolysaccharide (1 microg/ml) or tumor necrosis factor (5 ng/ml). The mRNA for both CCRL2A and CCRL2B were expressed in cytokine-stimulated neutrophils. Cells expressing either of these splice variants migrated in response to a fraction of RA SF. CONCLUSION: CCRL2 expression is up-regulated on synovial neutrophils of RA patients. Inflammatory products present in the SF activate this receptor, indicating that CCRL2 is a functional receptor that may be involved in the pathogenesis of RA.

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Language：English   Publisher：FEDERATION AMER SOC EXP BIOL  

DOI： 10.1002/art.20275

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL MUNKSGAARD  

BACKGROUND: In temporomandibular joint (TMJ) arthritis, knowledge is limited about the source of the inflammatory mediators. The aim of this study was to investigate the immunohistochemical role of tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) in the development of the antigen-induced arthritis of the rabbit TMJ.
METHODS: Unilateral TMJ arthritis was induced in 28 adult rabbits. From 6 h to 6 weeks after induction of arthritis, the topology of TNF-alpha and IL-8 was observed.
RESULTS: Positive reaction for TNF-alpha of synovial cells was observed within 3 days after induction and at 3 weeks after induction. TNF-alpha positive vascular endothelial cells and chondrocytes were identified throughout the observation period. IL-8 was detected only during the acute stage.
CONCLUSIONS: The cytokines TNF-alpha and IL-8 were observed in specific cells depending on the stage. TNF-alpha was particularly related with angiogenesis and cartilage destruction and IL-8 was involved in the acute stage of inflammation.

DOI： 10.1111/j.1600-0714.2004.00008.x

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Authorship：Lead author,　Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Stat3 is a transcription factor mediating anti-inflammatory properties of IL-10. In the present study, we demonstrate a pivotal role of Stat3 expressed in innate immune cells during septic peritonitis induced by cecal ligation and puncture (CLP). Mice with targeted disruption of Stat3 in macrophages and neutrophils were succumbed to septic peritonitis induced by CLP. The mice displayed an excessive local and systemic inflammation relative to the control mice, an event that was accompanied by substantial increases in the level of multiple cytokines. Hepatic and renal injury was significantly exacerbated in mice with Stat3 deficiency. Despite enhanced inflammatory responses, the mice failed to facilitate bacterial clearance as compared with the control mice. In addition, the mice exhibited an increased lethality after i.p. inoculation of live bacteria recovered from CLP-mice. In vitro, resident peritoneal macrophages from mice with Stat3 deficiency impaired bactericidal activity relative to the control whereas productions of inflammatory cytokines were significantly augmented when cells were stimulated with a synthetic lipopeptide, macrophage-activating lipopeptide-2 and LPS. Elicited macrophages and neutrophils with Stat3 deficiency also impaired bactericidal activity as compared with those with Stat3. Lysosomal enzyme release, an effector molecule for bacterial clearance, was significantly decreased in elicited leukocytes with Stat3 deficiency while increasing the production of inflammatory cytokines. Altogether, these results suggest that macrophage/neutrophil-specific STAT3 is crucial in not only modulating multiple organ failure associated with systemic inflammation but also intensifying the bactericidal activity, which highlight the significance of cell-specific Stat3 in the protective immunity during sepsis.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Purpose: To investigate the cell populations in diffuse lamellar keratitis (DLK) infiltration after laser in situ keratomileusis and the possible mechanism underlying the infiltration.
Setting: Department of Ophthalmology, Tokyo Dental College, Chiba, Japan.
Methods: To develop DLK in rabbit eyes, 25 muL of lipopolysaccharide (LPS) solution at a concentration of 50 mug/mL was applied to the stromal bed beneath corneal flaps. For control rabbits, phosphate-buffered saline was applied. Postoperative examination by slitlamp microscopy was performed for 3 days after surgery. Rabbit eyes were excised and examined for histopathology with hematoxylin and eosin staining. Immunohistochemical analysis for interleukin (IL)-8 was performed.
Results: Diffuse lamellar keratitis-like inflammation composed mainly of neutrophils was reproduced by LIDS instillation in rabbit eyes. In eyes with severe inflammation, IL-8 immunoreactivity was found in the stromal keratocytes and infiltrating neutrophils.
Conclusions: The major cell type in the DLK infiltration induced by LPS instillation in rabbit eyes was the neutrophil. Interleukin-8, a prototype of CXC chemokine produced by keratocytes and neutrophils, may contribute to the development of DLK. (C) 2003 ASCRS and ESCRS

DOI： 10.1016/S0886-3350(03)00496-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY, INC  

The effects of a monoclonal antibody (mAb) to tumor necrosis factor-alpha (TNF-alpha) were examined in a rabbit model of endotoxic shock. Intravenous administration of lipopolysaccharide (100 mug/kg/hr) for 6 hours (n = 11) increased TNF-alpha levels. Fibrinogen was partially consumed, and fibrin deposits were seen in kidney and lungs at 24 hours. Mortality at 24 hours was 64%. Levels of interleukin-8 (aka CXCL-8) were notably increased. Mean arterial pressure (MAP) and leukocyte counts decreased, whereas creatinine levels were enhanced. The anti-TNF-alpha mAb (20 mg/kg i.v. bolus + 5 mg/kg/h Lv. for the first 90 minutes) (n = 10) efficiently inhibited the TNF-activity. Rabbits exhibited lower CXCL-8 levels; MAP improved, the decrease in leukocyte counts was partially prevented and creatinine levels were lower, but fibrinogen, fibrin deposits in kidneys and lungs and mortality, 55%, were similar to the LPS group. Rabbits that did not survive exhibited lower fibrinogen levels, more fibrin in kidneys and lungs and higher CXCL-8 and creatinine levels than survivors, while there were no differences in TNF-alpha, MAP and leukocytes. Thus, the inhibition of TNF-alpha, although beneficial through lowering CXCL-8 levels, is not enough to improve the outcome, which could be partly due to the inability to prevent the fibrin deposits formation in kidneys and lungs.

DOI： 10.1067/mlc.2003.32

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Language：English   Publishing type：Part of collection (book)   Publisher：CRC Press  

The clinical manifestations of pulmonary granulomatous diseases are usually the consequence of long-term leukocyte elicitation and activation, resulting in chronic tissue inflammation and lung injury (1). Most interstitial granulomatous diseases in the lung are difficult to treat, requiring therapies that may seriously compromise the immunologic and physiologic integrity of the patient. Historically, the therapeutic approach to the treatment of infectious granulomatous disease has been to target the known infectious agent, while treatment of idiopathic granulomatous diseases has usually targeted immune/inflammatory cell function. Once the pulmonary disease is diagnosed, antimicrobial agents are used to treat the former, while immunosuppressive agents are usually used to treat the latter disease states (2,3). Unfortunately, the clinical management of these diseases does not necessarily ablate the subsequent pathology, which is observed in certain patients. This is especially true in difficult clinical cases, such as drug-resistant mycobacterial diseases or progressive sarcoidosis refractory to corticosteroids (2). Thus, the limited therapeutic options, which are available to effectively manage patients with granulomatous lung disease, may reflect the limited understanding of the mechanisms underlying these chronic diseases.

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Authorship：Lead author,　Last author,　Corresponding author  

DOI： 10.1016/S0531-5131(03)00236-X

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

FR167653 inhibits the production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, powerful inducers of CXC chemokines IL-8 and growth related oncogene (GRO)-alpha. The production of IL-8 and GRO-alpha was investigated and the effects of FR167653 were examined in a rabbit model of endotoxin shock. Male New Zealand rabbits were given endotoxin at a dose sufficient to induce DIC. Three groups of rabbits received FR167653 at different doses. TNF-alpha, IL-1beta, IL-8, and GRO-alpha levels were measured, several pathologic features were evaluated, and the results were compared with those obtained in control rabbits, which received only endotoxin. Endotoxin increased serum levels of IL-8 and GRO-alpha. which were associated with hypotension, renal dysfunction, and mortality, peaking at 4 It. FR167653 improved mortality, an event that was associated with decreased levels of not only TNF-alpha and IL-1beta but also IL-8 and GRO-alpha. TNF-alpha peaked at 2 h, at a time point before IL-8 and GRO-alpha reached their peak, and the TNF-alpha level was tightly correlated with that of IL-8 and GRO-alpha. Altogether, these data suggest the possible involvement of IL-8 and GRO-a in endotoxin shock, and FR167653 may foster a beneficial outcome in part by modulating the chemokines level by inhibiting TNF-alpha and IL-1beta. (C) 2002 Elsevier Science (USA).

DOI： 10.1006/exmp.2002.2467

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Macrophages are considered essential for herniated disc resorption, and chemokines may play a role in their recruitment. Here we demonstrate that intervertebral disc cells are capable of producing monocyte chemoattractant protem-1 (MCP-1), a CC chemokine that is chemotactic for macrophages. Nucleus pulposus cells and anulus fibrosus cells were harvested from intervertebral discs of healthy rabbits, and the cells were stimulated with either interleukin (IL)-1beta or tumor necrosis factor (TNF)alpha. Reverse transcriptase polymerase chain reaction demonstrated that IL-1beta and TNFalpha induced mRNA expression for MCP-1 in nucleus pulposus and anulus fibrosus cells. Protein concentrations of MCP-1 in the culture supernatants were quantitated by fluoroimmunoassay, which showed that nucleus pulposus and anulus fibrosus cells dose- and time-dependently produced MCP-1 after IL-1beta- and TNFalpha-stimulation, an event that was completely abrogated by IL-1 receptor antagonist and anti-TNFalpha monoclonal antibody, respectively. Nucleus pulposus cells produced significantly higher levels of MCP-1 than did anulus fibrosus cells. Immunohistochemically, the intensity of MCP-1 positive cells in nucleus pulposus cells was stronger than that in anulus fibrosus cells. Altogether, our data clearly demonstrated the production of MCP-1 in intervertebral disc cells, suggesting the possible involvement of disc cells in an early stage of macrophage infiltration. (C) 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0736-0266(02)00060-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN  

The plasminogen activator inhibitor-1 (PAI-1)-dependent fibrinolytic inhibition occurring in endotoxemia contributes to disseminated intravascular coagulation (DIC). Previous findings suggest that tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) are responsible for the increase in the level of PAI-1. These observations usually arose from mild endotoxemia models. We analyzed the effect of FR167653, an inhibitor of the TNF-alpha/IL-1beta production, on the PAI-1 levels in rabbits given endotoxin at a dose sufficient to induce DIC: the steep plasma PAI-1 increase was not attenuated by FR167653, in spite of achieving efficient inhibition of the TNF-alpha production. No IL-1beta was detected during endotoxemia. These results suggest that PAI-1 increase might be independent of TNF-alpha and IL-1beta. If these findings applied to humans, therapeutic intervention directing these cytokines would not be useful for the treatment of fibrinolysis in patients with severe sepsis.

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Accumulation of neutrophils is a prominent feature of gouty arthritis in which CXC chemokines may play a role. Recently, we have shown that IL-8 (CXCL8) contributes to neutrophil influx in a rabbit model of gouty arthritis. Here, we demonstrate that growth-related oncogene-a (GROalpha) (CXCL1), a prototype of CXC chemokine, is also involved in this process. GROalpha level in the joints peaked at 2 hours after intra-articular injection of monosodium urate crystals, at a time before the neutrophil influx reached the maximal level (9 hours). Once decreased, the level increased and reached the second peak at 9 hours. The kinetics was comparable to that of IL-8. Administration of anti-GROalpha mAb attenuated the neutrophil influx at the same level as did the anti-IL-8 IgG, and combination of these antibodies enhanced the inhibition, resulting in a 33% reduction. Interaction of GROalpha with TNFalpha, IL-1beta, and IL-8 was next investigated by injecting antibodies or receptor antagonist with monosodium urate crystals. Administration of anti-TNFalpha mAb did not alter GROalpha level at 2 hours, but inhibited the levels 9 hours after the injection. Treatment with either IL-1 receptor antagonist or anti-IL-8 IgG resulted in decreased levels of GROalpha at 2 and 9 hours. Neutralization of GROalpha with anti-GROalpha mAb did not alter TNFalpha, IL-1beta, and IL-8 levels at their peak (2 hours), but decreased the second peak of IL-1beta (9 hours) and IL-8 (12 hours). These results provide evidence that GROalpha as well as IL-8 are involved ad eundem in the neutrophil infiltration in this model. IL-1 and IL-8, but not TNFalpha, are responsible in part for the initial phase of GROalpha, whereas these cytokines induce GROalpha in a late phase. GROalpha does not seem to initiate TNFalpha, IL-1beta, and IL-8, in an early phase, but induces IL-1beta and IL-8 in a late phase.

DOI： 10.1097/01.LAB.0000029206.27080.D2

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Leukocyte interactions with vascular endothelium are an initial step for leukocyte entry into infectious foci where endothelial selectins may play a key role. Infiltrating leukocyte is essential for bacterial clearance, suggesting that endothelial selectins would be important in host defense against microorganisms. To address this, E-, P-, and E/P-selectiti-deficient mice (E-/-, P-/-, E/P-/-) and wild-type (WT) mice underwent cecal ligation and puncture (CLP). Neither leukocyte infiltration nor bacterial load in the peritoneum was altered in E-/-, P-/- and E/P-/- mice compared to WT mice. However, E-/-, P-/- and E/P-/- mice were resistant to the lethality induced by CLP. At the mechanistic level, E-/-, P-/-, and E/P-/- mice did not develop renal dysfunction, a possible cause of death during sepsis. The serum level of interleukin-13 in E`, P-/-, and E/P-/- mice that had undergone CLP was higher than that in WT mice, whereas levels of macrophage inflammatory protein-2, KC in serum, and KC in kidney were lower than those in WT mice. These experiments demonstrate that endothelial selectin-mediated leukocyte rolling is not required for leukocyte entry in septic peritonitis and that endothelial selectins may affect mice survival during sepsis by influencing the cytokine profiles. (C) 2002 Elsevier Science.

DOI： 10.1006/exmp.2001.2416

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Monocyte/macrophage infiltration to the arterial wall is an initial step in atherosclerosis, and monocyte chemoattractant protein-1 (MCP-1) is thought to play a central role in the recruitment of these cells. In the present study, we examined the role of local expression of MCP-1 at the vessel wall in the initiation and development of atherosclerosis. We transfected the cDNA encoding rat MCP-1 into the vessel wall of the rabbit carotid artery with the use of the hemagglutinating virus of Japan (HVJ)-liposome method. The rabbits were divided into the following groups: (1) those fed normal chow and transfected with MCP-1-HVJ, (2) those fed a high cholesterol diet (1% cholesterol) and transfected with MCP-1-HVJ, and (3) those fed a high cholesterol diet and transfected with control-HVJ. Prescribed diets were started 2 weeks before transfection and were continued for another 2 weeks. In group I, vascular lesion formation was not found, and anti-rabbit monocyte/macrophage antibody (RAM-11) staining for monocytes/macrophages was negative, although anti-rat MCP-1 antibody (R-17) staining for rat MCP-1 was positive mainly in endothelial cells. Cholesterol feeding increased plasma cholesterol levels to 1801+/-444 mg/dL in group 2. In group 2, all rabbits displayed neointimal formation with infiltration of RAM-11-positive cells, and a part of the lesion was also positive for Sudan III lipid staining. In group 3, hypercholesterolemia did not induce the infiltration of monocytes/ macrophages and subsequent lesion formation in the vessel wall despite definite upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 on the endothelium. To initiate atherosclerotic changes, local MCP-1 overexpression at the vessel is not sufficient, and activation of other factors induced by hypercholesterolemia is required.

DOI： 10.1161/hq0102.102278

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Interleukin-8 (IL-8: CXCL8) and growth related oncogene alpha (GROalpha: CXCL1) are members of the CXC chemokines. In the present study, we explored the functional distinction between these CXC chemokines in the regulation of neutrophil infiltration. Injection of either rabbit IL-8 or GROalpha (10 mug each) into rabbit knee joints resulted in a massive neutrophil infiltration in the joints. At their peak time point (6 hours), the number of neutrophils induced by IL-8 was more than that induced by GROalpha. Each chemokine induced the other chemokine in the joints. TNFalpha activity was induced in the joints after administration of GROalpha, but not IL-8. Treatment with anti-GROalpha mAb and/or anti-TNFalpha mAb failed to inhibit IL-8-induced neutrophil infiltration. In contrast, either anti-IL-8 IgG or anti-TNFalpha mAb decreased GROalpha-induced response, and the inhibition was further enhanced by coadministration of these antibodies. Thus, it appears that IL-8 acts directly, whereas GROalpha acts indirectly, in part, on neutrophil infiltration. The distinct difference in TNFalpha production between IL-8 and GROalpha was further investigated. In vitro, GROa induced TNFalpha activity in cultured synovial cells, the cells producing TNFalpha in the joints after GROalpha-injection. However, IL-8 failed to produce TNFalpha activity from the cells, although equivalent levels of the mRNA expression were induced by IL-8 as compared with GROalpha. When recombinant rabbit TNFalpha was incubated with synovial fluids obtained at 2 hours after IL-8 injection, the resultant TNFalpha activity was significantly decreased, an event that was completely restored by a serine protease inhibitor, phenylmethylsulphonyl fluoride (PMSF). Furthermore, TNFalpha activity was unveiled in the joints when IL-8 was intra-articularly injected with PMSF. These data suggest that TNFalpha is degraded by serine protease(s) in the case of IL-8. Taken together, the data clearly demonstrate the functional distinction between IL-8 and GROalpha, which may influence the inflammatory responses.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Glucocorticoids are the most potent and widely used anti-inflammatory agents, but they are not particularly effective against early phase of acute respiratory distress syndrome. We investigated whether methylprednisolone, a synthetic glucocorticoid, could inhibit increase of phospholipase A(2) activity in the lung and lead to protection against a model of acute respiratory distress syndrome in rabbits. Infusion of oleic acid (0.1 ml/kg/h, i.v. for 2 h) provoked pulmonary hemorrhage and edema, protein leakage and massive neutrophil infiltration, resulted in severe hypoxemia and impaired lung compliance, accompanying the increase of phospholipase A(2) activity and interleukin-8, and degradation of surfactant in the bronchoalveolar lavage fluid. Infusion of methylprednisolone (60 mg/kg/h, i.v. for 30 min before the oleic acid and then 0.5 mg/kg/h, i.v, for 6 h) did not improve the above described lung injury induced by oleic acid, nor did it suppress phospholipase A(2) activity and degradation of surfactant in bronchoalveolar lavage fluid, while it strongly reduced interleukin-8 levels in both plasma and bronchoalveolar lavage fluid. We conclude that methylprednisolone did not attenuate oleic acid-induced acute lung injury and this can be explained partly by its failure to reduce the increase of phospholipase A(2) activity and the surfactant degradation in the lung, which might also account for its clinical ineffectiveness against early acute respiratory distress syndrome. (C) 2001 Elsevier Science B.V All rights reserved.

DOI： 10.1016/S0014-2999(01)01507-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The aim was to investigate joint perfusate levels of interleukin-1 beta (IL-I beta) in antigen-induced monoarthritis of the rabbit temporomandibular (TMJ) and knee joints. Twenty-four adult male New Zealand White rabbits were divided into three groups: a control group as well as TMJ arthritis and knee joint arthritis groups. After sensitization, unilateral arthritis was induced by intra-articular injection with ovalbumin and the contralateral joint was injected with saline 3 weeks after induction of arthritis. Joints were then perfused continuously with saline and samples were collected at 10-min intervals over a 50-min period. The IL-1 beta concentrations in the samples were then analyzed. After killing the animals, the joints were examined histologically. The IL-1 beta concentrations in the samples from the arthritic TMJs and knee joints were significantly higher than in the saline-injected and the control joints. Histological signs of chronic arthritis of similar severity were;found in both joints. The IL-1 beta levels in the samples from the arthritic TM and knee joints correlated with the histological severity of the arthritis, including pannus formation. In conclusion, this study shows that IL-1 beta is released in the synovium of rabbit TMJs and knee joints during antigen-induced arthritis, and that high IL-1 beta levels in synovial fluid are associated with histological signs of inflammation including, pannus tissue formation. (C) 2001 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0003-9969(01)00009-7

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Chemokines constitute a large family of chemotactic cytokines that belong to a super-gene family of 8-10 kDa proteins. The chemokines are considered to be primarily beneficial in host defense against invading pathogens. However, the reactions induced by chemokines can be occasionally excessive, resulting in a harmful response to the host. Recent studies in chemokine biology have elucidated that chemokines are involved in the initiation, development, and maintenance of numbers of diseases including lung diseases. In addition to its chemotactic activity, evidence suggests that chemokines can modify the outcome of the cell-mediated immune responses by altering the Th1/Th2 cytokine profile. Chemokines are also capable of dictating the direction of specific immune responses. Chemokine action is mediated by a large super-family of G-protein coupled receptors, and the receptors are preferentially expressed on Th1/Th2 cells. Certain chemokine receptors are constitutively expressed in immune surveying cells such as dendritic cells and naive T cells. The corresponding chemokines are present in normal lymphoid tissues, suggesting a role of chemokines/receptors in cell homing and cell-cell communication in lymphoid tissue that can be an initial step for immune recognition. Thus, comprehension of the chemokine biology in immune responses appears to be fundamental for understanding the pathogenesis of T cell-mediated immune responses. The following review will highlight the current insight into the role of chemokines and their receptors in the cell-mediated immune response, with a special focus on lung diseases. (C) 2001 Wiley-Liss, Inc.

DOI： 10.1002/jemt.1096

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective: We attempted to determine whether group IIA secretory phospholipase A(2) (sPLA(2)-IIA) blockade after the onset of lung injury exerted therapeutic efficacy in the treatment of oleic acid (OA)-induced acute lung injury by using S-5920/LY315920Na, a novel specific inhibitor of sPLA(2)-IIA, with special interest in the changes of lung surfactant.
Design:Prospective animal study.
Setting: University laboratory.
Subjects: Forty Japanese white rabbits.
Interventions: The rabbits, under anesthesia, were endotracheally intubated and mechanically ventilated and then were divided into the following groups: OA + vehicle groups, intravenous infusion of OA for the first 2 hrs (0.1 mL . kg(-1). hr(-1)) with the addition of vehicle (1 or 2 hrs after OA administration, each n = 9, total 18 rabbits); OA + S-59201/Y315920Na groups, treated identically to the OA control with the addition of S-5920/LY315920Na (1 mg/kg bolus followed by infusion at 0.5 mg . kg(-1). hr(-1)) after OA (1 or 2 hrs after OA administration, each n = 9, total 18 rabbits); saline control groups, treated with saline instead of OA with the addition of vehicle (1 hr after OA administration, 4 rabbits). Arterial blood gas, lung mechanics, lung inflammation, lung surfactant phospholipids, and production of inflammatory mediators in the lung were measured.
Measurements and Main Results:Treatment with S-5920/ LY315920Na 1 hr after OA infusion, but not 2 hrs after infusion, significantly attenuated the lung injury, as estimated by hypoxemia, decreased lung compliance, pulmonary edema, and vascular permeability. The therapeutic efficacy was similar to that found in our previous pretreatment study. The treatment after 1 hr dramatically inhibited OA-induced surfactant degradation in the bronchoalveolar lavage fluid (BALF), without affecting the concentrations of thromboxane A(2), leukotriene B-4, and interleukin-8 in BALF. The degree of surfactant degradation in BALF paralleled well with the severity of the lung injury. Furthermore, recombinant human sPLA(2)-IIA reproduced the similar hydrolysis pattern of isolated surfactant in vitro, which was inhibited by S-5920/ LY315920Na.
Conclusions:Our results indicate that therapeutic blockade of sPLA(2)-IIA ameliorated lung dysfunction via protection of surfactant degradation in an animal model of acute lung injury, and they suggest a new strategy in treating clinical acute lung injury.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROCKEFELLER UNIV PRESS  

Signal transducer and activator of transcription (Stat)4 and Stat6 are transcription factors that provide type 1 and type 2 response, respectively. Here, we explored the role of Stat4 and Stat6 in innate immunity during septic peritonitis. Stat4(-/-) and Stat6(-/-) mice were resistant to the lethality compared with wild-type (WT) mice. At the mechanistic level, bacterial levels in Stat6(-/-) mice were much lower than in WT mice, which was associated with increased peritoneal levels of interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, macrophage-derived chemokine (MDC), and C10, known to enhance bacterial clearance, In Stat4-/- mice, hepatic inflammation and injury during sepsis were significantly ameliorated without affecting local responses. This event was associated with increased hepatic levels of IL-10 and IL-13, while decreasing those of macrophage inflammatory protein (MIP)-2 and KC. Sepsis-induced renal injury was also abrogated in Stat4(-/-) mice, which was accompanied by decreased renal levels of MIP-2 and KC without altering IL-10 and IL-13 levels. Thus, Stat6(-/-) and Stat(4-/-) mice appeared to be resistant to septic peritonitis by enhancing local bacterial clearance and modulating systemic organ damage, respectively, via balancing cytokine responses. These results clearly highlight an important role of local type 1 and systemic type 2 cytokine response ill protective immunity during sepsis, which can be regulated by Stat proteins.

DOI： 10.1084/jem.193.6.679

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

The contribution of neutrophils to lethal sensitivity and cytokine balance governing T1 and T2 host responses was assessed in a murine model of Legionella pneumophila pneumonia, Neutrophil depletion by administration of granulocyte-specific mAb RB6-8C5 at 1 day before infection rendered mice - 100-fold more susceptible to lethal pneumonia induced by L, pneumophila. However, this treatment did not alter early bacterial clearance, despite a substantial decrease in neutrophil influx at this time point. Cytokine profiles in the lungs of control mice demonstrated strong T1 responses, characterized by an increase of IFN-gamma and IL-12, In contrast, neutrophil-depleted mice exhibited significantly lower levels of IFN-gamma and IL-12, and elevation of T2 cytokines, IL-4 and IL-10, Immunohistochemistry of bronchoalveolar lavage cells demonstrated the presence of IL-12 in neutrophils, but not alveolar macrophages, Moreover, IL-12 was detected in lavage cell lysates by ELISA, which was paralleled to neutrophil number. However, intratracheal administration of recombinant murine IL-12 did not restore resistance, whereas reconstitution of IFN-gamma drastically improved bacterial clearance and survival in neutrophil-depleted mice. Taken together, these data demonstrated that neutrophils play crucial roles in primary L, pneumophila infection, not via direct killing but more immunomodulatory effects. Our results suggest that the early recruitment of neutrophils may contribute to T1 polarization in a murine model of L. pneumophila pneumonia.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

The mechanisms underlying the therapeutic efficacy of erythromycin (EM) in diffuse panbronchiolitis (DPB) was investigated. For this purpose, an experimental rabbit model of DPB induced by Pseudomonas aeruginosa inoculation was employed. Daily administration of EM (3 mg(.)kg(.)day(-1)) led to an increase in the number of macrophages in bronchoalveolar lavage fluid (BALF) at an early phase, while reducing the size of granulomatous lesions at the late phase without affecting the number of viable bacteria recovered from the infected lung.
Reverse transcriptase polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA) and immunohistochemical studies showed that monocyte chemoattractant protein (MCP)-1 was produced in both BALF and infected lung. EM treatment resulted in a significant increase in the level of MCP-1 in BALF, while reducing that of tumour necrosis factor (TNF)-alpha, interleukin (IL)-beta and IL-beta. EM also increased MCP-1 messenger ribonucleic acid (mRNA) and protein expression in the infected lung. MCP-1 blockade abolished the protective effect of EM, as neutralization of MCP-I with anti-MCP-l antibodies reduced the E;CZ-induced increase in the number of macrophages in BALF, and augmented size of the granulomatous lesions, as compared to control.
The results of the present study suggest that erythromycin attenuates the pulmonary granuloma formation, at least in part, by increasing the production of monocyte chemoattractant protein-1.

DOI： 10.1183/09031936.01.17303600

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Language：Japanese   Publisher：(公財)日本感染症医薬品協会  

び漫性汎細気管支炎実験モデルにおけるマクロファージの浸潤と単球化学誘導蛋白(MCP)-1の産生に対するエリスロマイシン(EM)の効果について検討した.EM治療群では1日目の気管支肺胞洗浄(BAL)液中および肺組織中のMCP-1と3日目のBAL液中のマクロファージ数が有意に増加し,肉芽腫様病変1個あたりの面積が有意に減少した.又,EM治療群において抗MCP-1抗血清による中和試験を行った結果,3日目のBAL液中のマクロファージ数は有意に減少し,肉芽腫様病変の面積は有意に拡大した.これらの結果から,EMはMCP-1の産生を調節して病変を改善させていることが示唆された

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIRKHAUSER VERLAG AG  

Objective and Design: To evaluate the mechanism whereby monocyte chemoattractant protein (MCP)-1 attracts monocytes in vivo.
Subjects: New Zealand white rabbits (175 rabbits) were used.
Treatment: LPS, MCP-1 or IL-8 was injected into knee joints. Antibodies against various cytokines or IL-1 receptor antagonist were injected to neutralize cytokine activities.
Methods: The numbers of leukocyte populations, levels of cytokines in joints were estimated.
Results: Partial inhibition of neutrophil influx with anti-IL-8 IgG (10 mug) suppressed LPS-induced macrophage influx by 43 +/- 8.5% (p&lt;0.05) without affecting the MCP-I level. Intraarticular injection of MCP-1 (1-30 &lt;mu&gt;g) induced macrophage influx. The event was accompanied by a small number of neutrophils in an early phase. Go-injection of IL-8 (1.0 mug) enhanced the MCP-1-induced macrophage infiltration (p&lt;0.01). In neutrophil-depleted rabbits, LPS failed to induce macrophage influx even though the MCP-1 level was maintained, and macrophage influx following exogenously administered MCP-1 was also dramatically inhibited.
Conclusions: Early events associated with neutrophil infiltration appear to be important for MCP-1 to induce a later macrophage influx in LPS-arthritis.

DOI： 10.1007/s000110050645

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

Previous studies have suggested that the C-C chemokine C10 is involved in the chronic stages of host defense reactions. The present study addressed the role of C10 in a murine model of septic peritonitis, induced by cecal ligation and puncture (CLP). Unlike other C-C chemokines, C10 levels in the peritoneal wash were increased approximately 30-fold above baseline levels at 48 h after CLP surgery. Immunoneutralization of peritoneal C10 Levels with polyclonal anti-C10 antiserum during CLP-induced peritonitis negatively impacted mouse survival over 4 days. In contrast,,when 500 ng of recombinant murine C10 was administered immediately after CLP surgery, the ii-day survival rate increased from 20% to over 60%. The C10 therapy appeared to facilitate a rapid and significant enhancement of the Levels of tumor necrosis factor alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-I) and a later increase in interleukin-13 (IL-13) levels in the peritoneal cavity. In vitro studies showed that the combination of IL-1 beta and C10 markedly augmented TNF-alpha synthesis by peritoneal macrophages and that C10 synthesis was induced in these cells following their exposure to IL-13, At 24 h after CLP surgery, only 25% of C10-treated mice were bacteremic versus 85% of the control group that exhibited dissemination of bacteria into the circulation, The Lack of bacteremia in C10-treated mice appeared to be related, in part, to in vitro evidence that C10 significantly enhanced the bacterial phagocytic activity of peritoneal macrophages. In addition, in vivo evidence suggested that C10 therapy significantly reduced the amount of material that leaked from the damaged gut. Taken together, the results of this study demonstrate that the C10 chemokine rapidly promotes disease resolution in the CLP model through its direct effects on the cellular events critically involved in host defense during septic peritonitis.

DOI： 10.1128/IAI.68.11.6108-6114.2000

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The aim of this study was to assess the acute effects of cigarette smoke exposure on cellular and cytokine profile in BAL fluids in an isolated perfused rabbit assay. The experimental animals were categorized into four groups: (1) unexposed controls and (2) cigarette smoke-exposed animals perfused with autologous whole blood; (3) unexposed controls and cigarette smoke-exposed; (4) cigarette smoke-exposed animals perfused with Krebs' Ringer solution containing 5% bovine serum albumin and glucose. Cigarette smoke induced an increase in total cell numbers (mainly alveolar macrophages in BAL fluids) and an increase in the permeability index of BAL. Levels of interleukin 8 were also significantly decreased in BAL fluids due to acute effects of cigarette smoke exposure. The most likely explanation for cigarette smoke-induced increase of inflammatory cells in BAL in lungs is because of the release of pre-existing cells from reservoirs within the lungs. The acute effects of cigarette smoke-induced increase of pulmonary epithelial permeability may also play an important role in the cellular recruitment into airspaces from the lung reservoirs. (C) 2000 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0034-5687(00)00147-X

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Macrophage-derived chemokine (MDC), a recently identified CC chemokine, has been regarded to be involved in chronic inflammation and dendritic cell and lymphocyte homing, In this study, we demonstrate a pivotal role for MDC during experimental sepsis induced by cecal ligation and puncture (CLP), Intraperitoneal administration of MDC (1 mu g/mouse) protected mice from CLP-induced lethality. The survival was accompanied by increased number of peritoneal macrophages and decreased recovery of viable bacteria from the peritoneum and peripheral blood. In addition, mice treated with an i.p. injection of MDC cleared bacteria more effectively than those in the control when 3 x 10(8) CFU live Escherichia coli was i.p. inoculated. Endogenous MDC was detected in the peritoneum after CLP, and neutralization of the MDC with anti-MDC Abs decreased CLP-induced recruitment of peritoneal macrophages and increased the recovery of viable bacteria from the peritoneum and peripheral blood. MDC blockade was deleterious in the survival of mice after CLP. In vitro, MDC enhanced the phagocytic and killing activities of peritoneal macrophages to E, coli and induced both a respiratory burst and the release of lysozomal enzyme from macrophages, Furthermore, MDC dramatically ameliorated CLP-induced systemic tissue inflammation as well as tissue dysfunction, which were associated in part with decreased levels of TNF-alpha, macrophage inflammatory proteins-1 alpha and -2, and KC in specific tissues. Collectively, these results indicate novel regulatory activities of MDC in innate immunity during sepsis and suggest that MDC may aid in an adjunct therapy in sepsis.

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Language：English   Publisher：BENTHAM SCIENCE PUBL BV  

Chemokines are involved in a number of pathological processes, and therefore represent important targets. However, it has also become apparent that chemokines have exciting therapeutic applications in inflammatory, infectious and cancer-related diseases. The following review will highlight the application of novel therapies including viral-encoded, recombinant, and genetically engineered chemokines to a number of diseases or disorders. Advances in the application of novel chemokine delivery procedures both at the research bench and the clinical bedside will also be discussed. Overall, the utilization of chemokines to prevent and treat disease has tremendous potential.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC  

Monocyte chemoattractant protein-1 is one of the major C-C chemokines that has been implicated in liver injury. The C-C chemokine receptor, CCR2, has been identified as the primary receptor that mediates monocyte chemoattractant protein-1 (MCP-1) responses in the mouse. Accordingly, the present study addressed the role of CCR2 in mice acutely challenged with acetaminophen (APAP). Mice genetically deficient in CCR2 (CCR2(-/-)) and their wild-type counterparts (CCR2(+/+)) were fasted for 10 hours before receiving an intraperitoneal injection of APAP (300 mg/kg), Liver and serum samples were removed from both groups of mice before and at 24 and 48 hours post APAP, Significantly elevated levels of MCP-1 were detected in liver samples from CCR2(+/+) and CCR2(-/-) mice at 24 hours post-APAP. Although CCR2(+/+) mice exhibited no liver injury at any time after receiving APAP, CCR2(-/-) mice exhibited marked evidence of necrotic and TUNEL-positive cells in the liver, particularly at 24 hours post-APAP, Enzyme-linked immunosorbent assay analysis of liver homogenates from both groups of mice at the 24 hours time point revealed that liver tissue from CCR2(-/-) mice contained significantly greater amounts of immunoreactive IFN-gamma and TNF-alpha. The in vivo immunoneutralization of IFN-gamma or TNF-alpha significantly attenuated APAP-induced liver injury in CCR2(-/-) mice and increased hepatic IL-13 levels. Taken together, these findings demonstrate that CCR2 expression in the liver provides a hepatoprotective effect through its regulation of cytokine generation during APAP challenge.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC  

Sepsis and septic syndrome represent an intense systemic response with multiple physiologic and immunologic abnormalities, leading to multiple organ failure. Recent investigations suggest that the critical conditions are balanced by endogenous cytokines. In the present study, we examined the involvement of endogenous monocyte chemoattractant protein (MCP)-1 in the regulation of cytokine production in tissue/organs in a murine model of acute septic peritonitis induced by cecal ligation and puncture (CLP). Initial studies showed that CLP induced elevated levels of MCP-1 in tissues, such as liver, lung, and kidney. To neutralize endogenous MCP-1, either anti-MCP-1 antibodies or control antibodies were intraperitoneally administered 2 h prior to CLP. Administration of anti-MCP-1 antibodies resulted in a decrease in the level of interleukin (IL)-13 in tissues, while increasing the level of tumor necrosis factor-alpha, compared to control. In addition, anti-MCP-1 treatment decreased the level of IL-12 and, in contrast, increased the level of IL-10 in specific tissues. These findings suggest that endogenous MCP-1 influences the cytokine balance in tissues in favor of antiinflammatory and immune-enhancing cytokines, probably protecting the host from tissue/organ damage during sepsis. (C) 2000 Academic Press.

DOI： 10.1006/exmp.1999.2296

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background. 21-aminosteroids (lazaroids) have demonstrated the protective effect against cerebral ischemic injury through the inhibition of lipid peroxidation. We examined whether lazaroids affected the production of proinflammatory and antiinflammatory cytokines in ischemic spinal cord injury model.
Materials. Anesthetized New Zealand white rabbits underwent a 20-minute infrarenal aortic cross-clamping (AXC) with pretreatment of either an intravenous 3 mg/kg lazaroid U74389G (group L; n = 10) or the same volume saline (group P; n = 10), Sham operation group (group S; n = 6) underwent only exposure of the aorta. Plasma concentrations of interleukin (IL)-8, -1 beta, -1 receptor antagonist (IL-1ra) and tumor necrosis factor (TNF)-alpha were measured at four time points. Functional assessment with Tarlov score at 24 and 48 hours after pretreatment, pathologic assessment of the spinal cord, and measurements of cytokine levels in the spinal cord were performed.
Results, The maximum elevation of plasma IL-8 and -1ra levels occurred at 1 hour after declamping in four measurement points, Plasma IL-8 and -1ra levels in group L were significantly lower than those in group P (*p &lt; 0.05), Plasma TNF alpha peaked at 5 minutes after declamping, but decreased afterwards. Plasma TNF alpha levels were not different among three groups, Spinal IL-8 levels in group L (0.98 +/- 0.34 ng/g tissue) were lower than those in group P (7.26 +/- 2.26 ng/g tissue) (*p &lt; 0.05), Spinal IL-1ra and TNF alpha were not significantly different Tarlov scare and pathologic assessment were better in group L,
Conclusions. Lazaroid U-74389G reduced the production of systemic IL-8 and -1ra and spinal IL-8 when AXC. caused spinal cord injury. These results indicate that lazaroids may attenuate ischemic endothelial cell injury or activation of leukocytes,
(C) 2000 by The Society of Thoracic Surgeons.

DOI： 10.1016/S0003-4975(99)01413-7

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

IL-13 has been shown to exert potent anti-inflammatory properties. In this study, we elucidated the functional role of endogenous IL-13 in a murine model of septic peritonitis induced by cecal ligation and puncture (CLP). Initial studies demonstrated that the level of IL-13 increased in tissues including liver, lung, and kidney, whereas no considerable increase was found int either peritoneal fluid or serum after CLP, Immunohistochemically, IL-13-positive cells were Kupffer cells in liver, alveolar macrophages in lung, and epithelial cells of urinary tubules in kidney. IL-13 blockade with anti-IL-13 Abs significantly decreased the survival rate of mice after CLP from 53% to 14% on day 7 compared with control, To determine the potential mechanisms whereby IL-13 exerted a protective role in this model, the effects of anti-IL-13 Abs on both local and systemic inflammation were investigated, Administration of anti-IL-13 Abs did not alter the leukocyte infiltration and bacterial load in the peritoneum after CLP hut dramatically increased the neutrophil influx in tissues after CLP, an effect that was accompanied by significant increases in the serum levels of aspartate transaminase, alanine transaminase, blood urea nitrogen, and creatinine, Tissue injury caused by IL-13 blockade was associated with increases in mRNA and the protein levels of CXC chemokines macrophage inflammatory protein-2 and KC as web as the CC chemokine macrophage inflammatory protein-1 alpha and the proinflammatory cytokine TNF-alpha. Collectively, these results suggest that endogenous IL-13 protected mice from CLP-induced lethality by modulating inflammatory responses via suppression of overzealous production of inflammatory cytokines/chemokines in tissues.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD  

The purpose of this study was to investigate the role and regulation of the CXC chemokine GRO and the interaction between GRO and IL-8 in LPS-induced uveitis in rabbits. Uveitis was induced by intravitreal injection of 100 ng of LPS in rabbits. After the LPS injection, GRO was produced in aqueous humor and peaked at 24 hr. Immunohistochemistry showed that ciliary epithelial cells were responsible for production of GRO. Blocking the activity of GRO by anti-GRO serum reduced LPS-induced aqueous neutrophil counts by 80%, but did not reduce the mononuclear cell counts or protein levels or IL-8 levels. Regulation of GRO production by TNF alpha, IL-1 and IL-8 was studied. Anti-TNF alpha mAb alone did not inhibit the 24 hr LPS induced GRO levels, whereas rrIL-1Ra inhibited the GRO production by 58%. The combination of anti-TNF alpha mAb and rrIL-1Ra inhibited 93 % of GRO production. Although treatment with anti-IL-8 IgG inhibited the neutrophil infiltration by 66%, treatment with this antibody did not inhibit GRO production.
Taken together, our results suggest that GRO is an essential mediator for neutrophil infiltration in LPS-induced uveitis in rabbits. Most of GRO production is mediated by TNF alpha and IL-1. GRO and IL-8 act in concert to mediate neutrophil infiltration. (C) 2000 Academic Press.

DOI： 10.1006/exer.1999.0778

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

The expression of chemokines during an immune response may participate in determining the intensity and type of the developing immune response. In the present study, we have examined the effect of overexpressing monocyte chemoattractant protein (MCP)-1 at the site of immunization during different stages of Th1- and Th2-type granulomatous responses. The overexpression of MCP-1 by MCP-1 adenovirus during the sensitization phase of the purified protein derivative Th1-type model significantly reduced the elicitation of the granulomatous response. In contrast, the overexpression of MCP-1 during the sensitization phase of the schistosome egg Ag Th2 response led to an enhanced granulomatous reaction. When cytokines were examined upon restimulation of splenocytes ex vivo, an altered cytokine profile was observed, as compared with control mice. IFN-gamma and IL-12 were significantly reduced in the purified protein derivative Th1-type response, whereas IL-10 and IL-13 were up-regulated in the schistosome egg Ag Th2-type response. The regulation of the immune response was further examined by using the MCP-1 adenovirus at later time points during the elicitation phase. When MCP-1 was overexpressed during the elicitation phase of the responses, neither the Th1-type nor the Th2-type granuloma was altered. Likewise, the cytokine profiles after restimulation of splenocytes ex vivo were unchanged, Thus, the function of MCP-1 may depend on the stage and type of immune response.

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Language：Japanese   Publisher：(一社)日本病理学会  

10歳女児.2歳時より繰り返し腫瘤切除を受けていた若年性多発性硝子化線維腫症(Juvenile hyaline fibromatosis)例で,本疾患は臨床像や病理組織像が極めて特徴的であるが,本邦での現在迄の報告は自験例を含めて13例と極めて稀である

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Language：Japanese   Publisher：西日本整形・災害外科学会  

66歳女,変形性膝関節症にてMg-II,セメントレス人工膝関節置換術を施行し,4年後より膝関節腫脹と疼痛を来し,X線像で大腿骨後顆にosteolysisを認めた.再置換術を施行した際,大腿骨内側顆後方と外側顆後方に各30×20×15mm,15×15×10mm大の骨欠損と,滑膜増生,metallosis,膝蓋骨面のHDP及びtibia surfaceの磨耗を認めた

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=1999&ichushi_jid=J00766&link_issn=&doc_id=19990330030010&doc_link_id=%2Fdl8ortra%2F1999%2F004802%2F010%2F0383-0390%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdl8ortra%2F1999%2F004802%2F010%2F0383-0390%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Galectin-9 (Gal-9) plays pivotal roles in the modulation of innate and adaptive immunity to suppress T-cell-mediated autoimmune models. However, it remains unclear if Gal-9 plays a suppressive role for T-cell function in non-autoimmune disease models. We assessed the effects of Gal-9 on experimental hypersensitivity pneumonitis induced by Trichosporon asahii. When Gal-9 was given subcutaneously to C57BL/6 mice at the time of challenge with T. asahii, it significantly suppressed T. asahii-induced lung inflammation, as the levels of IL-1, IL-6, IFN-gamma, and IL-17 were significantly reduced in the BALF of Gal-9-treated mice. Moreover, co-culture of anti-CD3-stimulated CD4 T cells with BALF cells harvested from Gal-9-treated mice on day 1 resulted in diminished CD4 T-cell proliferation and decreased levels of IFN-gamma and IL-17. CD11b(+)Ly-6C(high)F4/80(+) BALF Mphi expanded by Gal-9 were responsible for the suppression. We further found in vitro that Gal-9, only in the presence of T. asahii, expands CD11b(+)Ly-6C(high)F4/80(+) cells from BM cells, and the cells suppress T-cell proliferation and IFN-gamma and IL-17 production. The present results indicate that Gal-9 expands immunosuppressive CD11b(+)Ly-6C(high) Mphi to ameliorate Th1/Th17 cell-mediated hypersensitivity pneumonitis.

DOI： 10.1002/eji.200939886

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Language：Japanese   Publisher：長崎大学  

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Authorship：Lead author   Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：Birkhauser Verlag Basel  

Studies have suggested the role of cytokines in inflammation, as determined by results obtained in vitro, or with assessments of clinical samples. However, extrapolation of in vitro results to an in vivo situation must be made with caution, and findings obtained from clinical samples tend to lack a causal relation between cytokines and inflammatory responses. Animal models of inflammation can be useful in understanding roles of cytokines at sites of inflammation. We examined the production kinetics and cellular sources of tumor necrosis factor alpha (TNFα), interleukin (IL)-1β, IL-8, and IL-1 receptor antagonist (IL-1Ra), and obtained evidence for the involvement of these cytokines in a rabbit model of arthritis induced by lipopolysaccharide (LPS). We also attempted to analyze the inflammatory cytokine network among TNFα, IL-1β, IL-8, and IL-1Ra. Understanding the role of cytokines in animal models paves the way to a better understanding of disease in humans.

DOI： 10.1007/s000110050304

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Language：Japanese   Publisher：日本サルコイドーシス  

DOI： 10.14830/jssog1987.16.21

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Other Link： http://search.jamas.or.jp/link/ui/1997140872

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=1996&ichushi_jid=J01133&link_issn=&doc_id=19961129050003&doc_link_id=10004798724&url=https%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F10004798724&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

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Language：Japanese   Publisher：公益社団法人 土木学会  

DOI： 10.2208/proce1989.42.721

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Language：Japanese   Publisher：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.42.340_2

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Authorship：Lead author  

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Language：Japanese   Publisher：The Japanese Society of Gastroenterology  

DOI： 10.11405/nisshoshi1964.90.1611

PubMed

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Authorship：Lead author   Language：English   Publisher：Biomedical Research Press  

DOI： 10.2220/biomedres.13.269

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Publisher：メジカルビュー社  

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Language：Japanese   Publisher：Hirosaki University  

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Language：Japanese   Publisher：West-Japanese Society of Orthopedics & Traumatology  

Sixty-seven patients had double-stay reconstruction using iliotibial tract for anterior cruciate ligament (ACL) injury. Thirty patients were evaluated at least 2 years postoperatively to assess the results and ability to return to sports.<br>Follow-up study consisted of an interview, clinical and radiological examinations. In 28 patients the complaint of giving way completely disappeared and in 2 patients they had experienced it several times during sports. N-test was negative in 26 patients and trace or apprehension in 4 patients.<br>To evaluate the instability in flexion, anterior drawer rate (ADR) was measured radiologically by a mid-point measurement method. The difference in ADR between the reconstructed and healthy knee was less than 5% in 20 patients. The range of motion was full or nearly full in all of patients.<br>Fifteen patients showed wasting of the thigh more than 1cm measured at 10cm above the proximal pole of the patella. Sports activity improved significantly and 90% of the patients returned to the sports. In conclusion, the results of double-stay reconstruction using iliotibial tract for ACL injury was satisfactory.

DOI： 10.5035/nishiseisai.40.16

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Language：Japanese   Publisher：West-Japanese Society of Orthopedics & Traumatology  

We recently had two rare cases of a stress fracture in the lower extremity. The first case was a 14-year-old sprinter who suffered a stress fracture of the medial malleolus. The second case was a 15-year-old baseball player who had an initial stress fracture in the femur and later stress fracture in the ipsilateral tibia. We shortly discussed about these cases.

DOI： 10.5035/nishiseisai.39.1470

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Language：Japanese   Publisher：The Japanese Society of Inflammation and Regeneration  

DOI： 10.2492/jsir1981.10.17

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Language：Japanese   Publisher：Japan Gastroenterological Endoscopy Society  

A case of anomalous union of the pancreatico-biliary ductal system (AUPBDS) with a fusiform dilatation of the common bile duct, in which the arrangement of the two ductal systems was demonstrated with endoscopic ultrasonography (EUS), was reported. A 34-aged male was admitted for a surgical treatment with congenital dilatation of the bile duct. ERCP revealed AUPBDS of biliary joining type with a common channel of 13 mm in length. The constricted part of the common bile duct that seemed to join the main pancreatic duct within the pancreatic parenchyma was demonstarated by conventional ultrasonography. With EUS, the junction of the two ducts was much more clearly depicted and located in the pancreatic parenchyma. In conclusion, EUS seemed to be one of the most useful methods in imaging the extramural junction of pancreatic and biliary ducts in AUPBDS.

DOI： 10.11280/gee1973b.31.961

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Language：Japanese   Publisher：West-Japanese Society of Orthopedics & Traumatology  

There are a few reports about surgery of foramen magnum tumors by the anterior approach. We report a case of foramen magnum meningioma who was treated by transoral extirpation and had a good result. A 77-year-old woman was admitted to the Kumamoto University Hospital on June 9th, 1988. 10 year prior to the admission she noticed the numbness in the hands and legs. In 1984 she suffered from pain and dysesthesia in the right chest. In May 1988 she could not walk at all. MRI disclosed an intradural and extramedullary tumor at the level of foramen magnum. The tumor was resected completely by transoral approach and a posterior occipito-C2 fusion by Luque rectangular rod was added. After the operation her pain in the right chest faded away and muscle strength improved gradually. Five months after the operation she is doing standing exercise.

DOI： 10.5035/nishiseisai.38.737

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Language：Japanese   Publisher：West-Japanese Society of Orthopedics & Traumatology  

We studied arthroscopically chondral lesions of 56 knees in 55 patients under 40 years of age with anterior cruciate ligament injuries. Chondral lesions were found in 23 knees. With the passage of time after injury, the frequency of chondral lesions increased and extent and grade of chondral lesions developed. In a group examined more than 3 months after injury, chondral lesions were not present in 4 knees with intact menisci. A presence of chondral lesions in femoral coridyle correlated with a presence of meniscal tear or meniscectomy on the same side. The higher activity after injury or reinjury made frequency with chondral lesions higher.

DOI： 10.5035/nishiseisai.37.100

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Language：English   Publisher：(一社)日本病理学会  

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Language：English   Publisher：(一社)日本病理学会  

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Language：English   Publisher：(一社)日本病理学会  

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Language：English   Publisher：(一社)日本病理学会  

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Language：English   Publisher：(一社)日本病理学会  

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Language：English   Publisher：(一社)日本病理学会  

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Language：English   Publisher：(一社)日本病理学会  

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Language：English   Publisher：(一社)日本癌学会  

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