Faculty Profiles - NAKAO Atsunori

Papers - NAKAO Atsunori

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【外科領域における嫌気性菌感染症】ガス壊疽デブリドマン後の広範囲軟部組織欠損の症例にβ-ヒドロキシ-β-メチルブチレート(HMB)、アルギニン(Arg)、グルタミン(Gln)配合飲料を用いた1例

寺嶋真理子, 中尾篤典, 橋本篤徳, 山田太平, 満保直美, 小谷穣治

日本外科感染症学会雑誌 9 ( 6 ) 691 - 696 2012.12

Language：Japanese Publisher：(一社)日本外科感染症学会

β-ヒドロキシルβ-メチルブチレート・アルギニン・グルタミン(HMB/Arg/Gln)配合飲料は蛋白の合成を促進し、分解を抑制するといわれている。今回、臀部の褥瘡感染を契機に発症したガス壊疽部のデブリドマン後の皮膚軟部組織欠損部加療中に、HMB/Arg/Gln配合飲料を経口投与した症例を経験したので報告する。症例は67歳女性。仙骨、右坐骨部褥瘡に感染を伴い右臀部から大腿部にガス壊疽が出現したため当センターに搬入となった。同日創部の開放、デブリドマンを行い、2日目よりHMB/Arg/Gln配合飲料の摂取を開始し、良好な創閉鎖につながった。ガス壊疽などの壊死性軟部組織感染症の治療として、感染壊死組織のデブリドマンと同時に欠損部の修復も重要である。HMB/Arg/Gln配合飲料を用いた代謝栄養学的アプローチは容易で有用な方法と思われた。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2012&ichushi_jid=J04188&link_issn=&doc_id=20130128230009&doc_link_id=%2Fdg9srgif%2F2012%2F000906%2F010%2F0691-0696%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg9srgif%2F2012%2F000906%2F010%2F0691-0696%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Preservation solution supplemented with biliverdin prevents lung cold ischaemia/reperfusion injury. Reviewed International journal

Ryujiro Sugimoto, Yugo Tanaka, Kentaro Noda, Tomohiro Kawamura, Yoshiya Toyoda, Timothy R Billiar, Kenneth R McCurry, Atsunori Nakao

European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 42 ( 6 ) 1035 - 41 2012.12

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

OBJECTIVES: Biliverdin (BV), one of the byproducts of heme catalysis through the heme oxygenase system, is a known scavenger of the reactive oxygen species. We hypothesized that adding BV to the perfusate and cold storage solution could protect rat lung grafts from oxidative injuries via its antioxidant efficacies. METHODS: Orthotopic left lung transplantation was performed in a syngenic Lewis-to-Lewis rat combination under 100% oxygen. Grafts were preserved in low-potassium dextran (LPD; Perfadex) at 4°C for 6 h with or without supplementation of 1 or 10 μM of BV into LPD. RESULTS: Prolonged cold storage and reperfusion resulted in a considerable deterioration of graft functions associated with massive apoptosis in the grafts after reperfusion. The untreated grafts exhibited the early up-regulations of mRNA for inflammatory mediators and an increase in a marker of lipid peroxidation, showing oxidative injuries. Although BV supplementation of LPD at a lower concentration (1 μM) did not improve the graft gas exchange, the grafts treated with BV (10 μM) showed a significant improvement of oxygenation and less inflammatory responses as well as reduced lipid peroxidation and apoptosis. Although the rapid activations of mitogen-activated protein kinases (MAPKs) were seen 30 min after reperfusion in the grafts stored in control LPD, BV treatment significantly reduced phosphorylated-MAPK protein expression. CONCLUSIONS: This study demonstrates that the exposure of the lung grafts to BV during cold storage can impart potent cytoprotective effects to lung cold ischaemia/reperfusion injury and significantly improve the lung graft function following extended cold preservation and transplantation by the mechanism of a reduction in oxidative injury and following inflammatory events.

DOI： 10.1093/ejcts/ezs298

A secure "double-check" technique of bedside post pyloric feeding tube placement using transnasal endoscopy. Reviewed

Atsunori Hashimoto, Munehiko Oya, Mika Iwano, Chisako Fuse, Tomoko Inoue, Taihei Yamada, Mariko Terashima, Takaaki Osako, Takahiro Ueda, Isamu Yamada, Atsunori Nakao, Joji Kotani

Journal of clinical biochemistry and nutrition 51 ( 3 ) 213 - 5 2012.11

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION

Enteral feeding has become an important means of providing nutritional support to seriously ill patients. Placement of the feeding tube through the pyloric ring and past the ligament of Treitz into the proximal jejunum is critical to reduce the risk of gastroesophageal regurgitation and microaspiration. We started utilizing transnasal endoscopy for intestinal feeding tube placement, placing enteral tubes for 40 patients between March 2008 and February 2009. Although we achieved a high success rate comparable to previous reports, we experienced several cases of failure, which was corrected with repeated endoscopy. Based on these experiences, we modified our method by adding a "double-check" transnasal endoscopy through the other nasal passage. After April 2010, we have placed the feeding tube by "double-check" method for all patients (more than 40 patients) who required transnasal endoscopic feeding tube placement. We have not experienced any misplacement in all these patients after 24 h later with 100% successful rate since the introduction of "double-check" procedure. We describe our experience with "double-check" transnasal endoscopic feeding tube placement, which we found to be a helpful adjunct, for patients in intensive care unit.

DOI： 10.3164/jcbn.12-35

The effect of donor treatment with hydrogen on lung allograft function in rats

Tomohiro Kawamura, Chien-Sheng Huang, Ximei Peng, Kosuke Masutani, Norihisa Shigemura, Timothy R. Billiar, Meinoshin Okumura, Yoshiya Toyoda, Atsunori Nakao

SURGERY 150 ( 2 ) 240 - 249 2011.8

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY-ELSEVIER

Background. Because inhaled hydrogen provides potent anti-inflammatory and antiapoptotic effects against acute lung injury, we hypothesized that treatment of organ donors with inhaled hydrogen during mechanical ventilation would decrease graft injury after lung transplantation.
Methods. Orthotopic left lung transplants were performed using a fully allogeneic Lewis to Brown Norway rat model. The donors were exposed to mechanical ventilation with 98% oxygen plus 2% nitrogen or 2% hydrogen for 3 h prior to harvest, and the lung grafts underwent 4 h of cold storage in Perfadex (Vitrolife, Goteborg, Sweden). The graft function, histomorphologic changes, and inflammatory reactions were assessed.
Results. The combination of mechanical ventilation and prolonged cold ischemia resulted in marked deterioration of gas exchange when the donors were ventilated with 2% nitrogen/98% oxygen, which was accompanied by upregulation of proinflammatory cytokines and proapoptotic molecules. These lung injuries were attenuated significantly by ventilation with 2% hydrogen. Inhaled hydrogen induced heme oxygenase-1, an antioxidant enzyme, in the lung grafts prior to implantation, which might contribute to protective effects afforded by hydrogen.
Conclusion. Preloaded hydrogen gas during ventilation prior to organ procurement protected lung grafts effectively from ischemia/reperfusion-induced injury in a rat lung transplantation model. (Surgery 2011;150:240-9.)

DOI： 10.1016/j.surg.2011.05.019

Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors Invited Reviewed

Ki-Mun Kang, Young-Nam Kang, Ihil-Bong Choi, Yeunhwa Gu, Tomohiro Kawamura, Yoshiya Toyoda, Atsunori Nakao

Medical Gas Research 1 ( 1 ) 1 - 11 2011

Language：English Publishing type：Research paper (scientific journal) Publisher：BioMed Central Ltd.

Background: Cancer patients receiving radiotherapy often experience fatigue and impaired quality of life (QOL). Many side effects of radiotherapy are believed to be associated with increased oxidative stress and inflammation due to the generation of reactive oxygen species during radiotherapy. Hydrogen can be administered as a therapeutic medical gas, has antioxidant properties, and reduces inflammation in tissues. This study examined whether hydrogen treatment, in the form of hydrogen-supplemented water, improved QOL in patients receiving radiotherapy. Methods. A randomized, placebo-controlled study was performed to evaluate the effects of drinking hydrogen-rich water on 49 patients receiving radiotherapy for malignant liver tumors. Hydrogen-rich water was produced by placing a metallic magnesium stick into drinking water (final hydrogen concentration
0.55∼0.65 mM). The Korean version of the European Organization for Research and Treatment of Cancer's QLQ-C30 instrument was used to evaluate global health status and QOL. The concentration of derivatives of reactive oxidative metabolites and biological antioxidant power in the peripheral blood were assessed. Results: The consumption of hydrogen-rich water for 6 weeks reduced reactive oxygen metabolites in the blood and maintained blood oxidation potential. QOL scores during radiotherapy were significantly improved in patients treated with hydrogen-rich water compared to patients receiving placebo water. There was no difference in tumor response to radiotherapy between the two groups. Conclusions: Daily consumption of hydrogen-rich water is a potentially novel, therapeutic strategy for improving QOL after radiation exposure. Consumption of hydrogen-rich water reduces the biological reaction to radiation-induced oxidative stress without compromising anti-tumor effects. © 2011 Kang et al
licensee BioMed Central Ltd.

DOI： 10.1186/2045-9912-1-11

Inhaled hydrogen gas therapy for prevention of lung transplant-induced ischemia/reperfusion injury in rats

Tomohiro Kawamura, Chien-Sheng Huang, Naobumi Tochigi, Sungsoo Lee, Norihisa Shigemura, Timothy R. Billiar, Meinoshin Okumura, Atsunori Nakao, Yoshiya Toyoda

Transplantation 90 ( 12 ) 1344 - 1351 2010.12

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

Background. Successful abrogation of ischemia/reperfusion (I/R) injury of lung grafts could significantly improve short- and long-term outcomes for lung transplant (LTx) recipients. Hydrogen gas has potent antioxidant and antiapoptotic properties and has been recently used in number of experimental and clinical studies. The purpose of this research was to investigate whether inhaled hydrogen gas could reduce graft I/R injury during lung transplantation. Methods. Orthotopic left LTxs were performed in syngenic Lewis rats. Grafts were perfused with and stored in low potassium dextran solution at 4°C for 6 hr. The recipients received 100% O2 or 98% O2 with 2% N 2, 2% He, or 2% H2 during surgery and 1 hr after reperfusion. The effects of hydrogen were assessed by functional, pathologic, and molecular analysis. Results. Gas exchange was markedly impaired in animals exposed to 100% O2, 2% N2, or 2% He. Hydrogen inhalation attenuated graft injury as indicated by significantly improved gas exchange 2 hr after reperfusion. Graft lipid peroxidation was significantly reduced in the presence of hydrogen, demonstrating antioxidant effects of hydrogen in the transplanted lungs. Lung cold I/R injury causes the rapid production and release of several proinflammatory mediators and epithelial apoptosis. Exposure to 2% H2 significantly blocked the production of several proinflammatory mediators and reduced apoptosis with induction of the antiapoptotic molecules B-cell lymphoma-2 and B-cell lymphoma-extra large. Conclusion. Treatment of LTx recipients with inhaled hydrogen can prevent lung I/R injury and significantly improve the function of lung grafts after extended cold preservation, transplant, and reperfusion. © 2010 by Lippincott Williams &amp
Wilkins.

DOI： 10.1097/TP.0b013e3181fe1357

Protective Effect of Carbon Monoxide Inhalation on Lung Injury After Hemorrhagic Shock/Resuscitation in Rats Reviewed

Fumitoshi Kanagawa, Toru Takahashi, Kazuyoshi Inoue, Hiroko Shimizu, Emiko Omori, Hiroshi Morimatsu, Shigeru Maeda, Hiroshi Katayama, Atsunori Nakao, Kiyoshi Morita

JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE 69 ( 1 ) 185 - 194 2010.7

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

Background: Hemorrhagic shock and resuscitation (HSR) induces pulmonary inflammation that leads to acute lung injury. Carbon monoxide (CO), a by-product of heme catalysis, was shown to have potent cytoprotective and anti-inflammatory effects. The aim of this study was to examine the effects of CO inhalation at low concentration on lung injury induced by HSR in rats.
Methods: Rats were subjected to HSR by bleeding to achieve mean arterial pressure of 30 mm Hg for 60 minutes followed by resuscitation with shed blood and saline as needed to restore blood pressure. HSR animals were either maintained in room air or were exposed to CO at 250 ppm for 1 hour before and 3 hours after HSR.
Results: HSR caused an increase in the DNA binding activity of nuclear factor-kappa B and activator protein-1 in the lung followed by the up-regulation of pulmonary gene expression of tumor necrosis factor-alpha, inducible nitric oxide synthase, and interleukin (IL)-10. HSR also resulted in an increase in myeloperoxidase activity and wet weight to dry weight ratio in the lung, and more prominent histopathologic changes including congestion, edema, cellular infiltration, and hemorrhage. In contrast, CO inhalation significantly ameliorated these inflammatory events as judged by fewer histologic changes, less up-regulation of inflammatory mediators, and less activation of nuclear factor-kappa B and activator protein-1. Interestingly, the protective effects against lung injury afforded by CO were associated with further increases in mRNA expression of IL-10 in the lung.
Conclusions: These findings suggest that inhaled CO at a low concentration ameliorated HSR-induced lung injury and attenuated inflammatory cascades by up-regulation of anti-inflammatory IL-10.

DOI： 10.1097/TA.0b013e3181bbd516

Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both. Reviewed International journal

Atsunori Nakao, David J Kaczorowski, Yinna Wang, Jon S Cardinal, Bettina M Buchholz, Ryujiro Sugimoto, Kimimasa Tobita, Sungsoo Lee, Yoshiya Toyoda, Timothy R Billiar, Kenneth R McCurry

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 29 ( 5 ) 544 - 53 2010.5

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

BACKGROUND: Recent advances in novel medical gases, including hydrogen and carbon monoxide (CO), have demonstrated significant opportunities for therapeutic use. This study was designed to evaluate the effects of inhaled hydrogen or CO, or both, on cold ischemia/reperfusion (I/R) injury of the myocardium. METHODS: Syngeneic heterotopic heart transplantation was performed in rats after 6 or 18 hours of cold ischemia in Celsior solution. Survival, morphology, apoptosis and marker gene expression were assessed in the grafts after in vivo inhalation of hydrogen (1% to 3%), CO (50 to 250 ppm), both or neither. Both donors and recipients were treated for 1 hour before and 1 hour after reperfusion. RESULTS: After 6-hour cold ischemia, inhalation of hydrogen (>2%) or CO (250 ppm) alone attenuated myocardial injury. Prolonged cold ischemia for 18 hours resulted in severe myocardial injury, and treatment with hydrogen or CO alone failed to demonstrate significant protection. Dual treatment with hydrogen and CO significantly attenuated I/R graft injury, reducing the infarcted area and decreasing in serum troponin I and creatine phosphokinase (CPK). Hydrogen treatment alone significantly reduced malondialdehyde levels and serum high-mobility group box 1 protein levels as compared with air-treated controls. In contrast, CO only marginally prevented lipid peroxidation, but it suppressed I/R-induced mRNA upregulation for several pro-inflammatory mediators and reduced graft apoptosis. CONCLUSIONS: Combined therapy with hydrogen and CO demonstrated enhanced therapeutic efficacy via both anti-oxidant and anti-inflammatory mechanisms, and may be a clinically feasible approach for preventing cold I/R injury of the myocardium.

DOI： 10.1016/j.healun.2009.10.011

Oral hydrogen water prevents chronic allograft nephropathy in rats. Reviewed International journal

Jon S Cardinal, Jianghua Zhan, Yinna Wang, Ryujiro Sugimoto, Allan Tsung, Kenneth R McCurry, Timothy R Billiar, Atsunori Nakao

Kidney international 77 ( 2 ) 101 - 9 2010.1

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

Reactive oxygen species (ROS) contribute to the development of interstitial fibrosis and tubular atrophy seen in chronic allograft nephropathy (CAN). As molecular hydrogen gas can act as a scavenger of ROS, we tested the effect of treatment with hydrogen water (HW) in a model of kidney transplantation, in which allografts from Lewis rats were orthotopically transplanted into Brown Norway recipients that had undergone bilateral nephrectomy. Molecular hydrogen was dissolved in water and recipients were given HW from day 0 until day 150. Rats that were treated with regular water (RW) gradually developed proteinuria and their creatinine clearance declined, ultimately leading to graft failure secondary to CAN. In contrast, treatment with HW improved allograft function, slowed the progression of CAN, reduced oxidant injury and inflammatory mediator production, and improved overall survival. Inflammatory signaling pathways, such as mitogen-activated protein kinases, were less activated in renal allografts from HW-treated rats as compared with RW-treated rats. Hence, oral HW is an effective antioxidant and antiinflammatory agent that prevented CAN, improved survival of rat renal allografts, and may be of therapeutic value in the setting of transplantation.

DOI： 10.1038/ki.2009.421

Orally administered nitrite attenuates cardiac allograft rejection in rats. Reviewed International journal

Jianghua Zhan, Atsunori Nakao, Ryujiro Sugimoto, Rajeev Dhupar, Yinna Wang, Zhiliang Wang, Timothy R Billiar, Kenneth R McCurry

Surgery 146 ( 2 ) 155 - 65 2009.8

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY-ELSEVIER

BACKGROUND: Recent studies have shown that nitrite serves as an endogenous reservoir of nitric oxide (NO), particularly in the presence of hypoxia and ischemia. We hypothesized that exogenous nitrite supplementation would protect cardiac allografts. METHODS: Fully allogeneic heterotopic heart transplantation was performed in LEW to BN combination under tacrolimus. Animals were given either regular or nitrite/nitrate (NOx)-low chow combined with regular water or water containing nitrite (50 mg/L) for 120 days continuously beginning 7 days before transplant. RESULTS: Serum nitrite/nitrate levels were significantly higher in animals given nitrite water for 30 days, and lower in the animals fed with NOx-low diet than those in animals who received standard diet. Supplementation of drinking water with nitrite enhanced heart graft survival to a median of >120 days from 49.5 days in animals fed a standard diet. In contrast, dietary NOx insufficiency resulted in significantly earlier rejection of allografts (30.5 days). In correlation with graft survival, mRNA levels for interferon-gamma in the spleen or tumor necrosis factor-alpha in the grafts were significantly less when animals were fed nitrite water compared with those without nitrite supplementation. CONCLUSION: These data demonstrate that dietary nitrite supplementation was significantly effective in preventing development of allograft rejection.

DOI： 10.1016/j.surg.2009.05.002

Mechanisms of Toll-like receptor 4 (TLR4)-mediated inflammation after cold ischemia/reperfusion in the heart. Reviewed International journal

David J Kaczorowski, Atsunori Nakao, Raghuveer Vallabhaneni, Kevin P Mollen, Ryujiro Sugimoto, Junichi Kohmoto, Brian S Zuckerbraun, Kenneth R McCurry, Timothy R Billiar

Transplantation 87 ( 10 ) 1455 - 63 2009.5

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

BACKGROUND: Toll-Like Receptor 4 (TLR4) signaling mediates early inflammation after cold ischemia-reperfusion (I/R). We hypothesized that the TLR4 coreceptor CD14, the intracellular adaptor proteins myeloid differentiation factor 88 (MyD88) and TIR domain-containing-adaptor inducing IFNbeta (TRIF) would be required for cold I/R induced inflammation. High mobility group box 1 (HMGB1) is a putative endogenous activator of TLR4. Therefore, we also assessed the contribution of HMGB1 in cold I/R induced inflammation. METHODS: Syngeneic heart transplants were performed in mice deficient in CD14, MyD88, TRIF, or wild-type mice. In other experiments, anti-HMGB1 neutralizing antibody or control IgG was administered at reperfusion. Donor hearts were subjected to 2 hr of cold ischemia and retrieved after 3 hr of reperfusion. RESULTS: After cold I/R, grafts revealed striking translocation of HMGB1 out of the nucleus in cardiac myocytes. Administration of an anti-HMGB1 neutralizing antibody resulted in reduced systemic interleukin (IL)-6, tumor necrosis factor alpha (TNFalpha), and intercellular adhesion molecule-1 (ICAM-1) messenger RNA (mRNA) levels (P< or =0.05). Compared with controls, CD14 knock-out (KO) mice exhibited significantly lower (P< or =0.05) systemic IL-6 and JE/monocyte chemotractant protein-1 levels after cold I/R. Intragraft TNFalpha and IL-1beta mRNA levels were also significantly lower (P< or =0.05) in CD14 KO grafts. MyD88 KO mice exhibited significantly lower (P< or=0.05) systemic IL-6 levels compared with control mice after cold I/R. Intragraft TNFalpha, IL-6, and ICAM-1 mRNA levels were also significantly lower (P< or =0.05) in MyD88 KO grafts. Significantly lower levels (P< or =0.05) of serum IL-6, monocyte chemotractant protein-1 as well as intragraft TNFalpha, IL-6, IL-1beta, and ICAM-1 were observed after cold I/R in TRIF deficient animals compared with controls. CONCLUSIONS: CD14, MyD88, TRIF, and HMGB1 contribute to the inflammatory response that occurs after cold I/R. These results provide insight into the mechanisms of TLR4-mediated inflammation after cold I/R.

DOI： 10.1097/TP.0b013e3181a36e5e

Therapeutic antioxidant medical gas. Reviewed

Atsunori Nakao, Ryujiro Sugimoto, Timothy R Billiar, Kenneth R McCurry

Journal of clinical biochemistry and nutrition 44 ( 1 ) 1 - 13 2009.1

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION

Medical gases are pharmaceutical gaseous molecules which offer solutions to medical needs and include traditional gases, such as oxygen and nitrous oxide, as well as gases with recently discovered roles as biological messenger molecules, such as carbon monoxide, nitric oxide and hydrogen sulphide. Medical gas therapy is a relatively unexplored field of medicine; however, a recent increasing in the number of publications on medical gas therapies clearly indicate that there are significant opportunities for use of gases as therapeutic tools for a variety of disease conditions. In this article, we review the recent advances in research on medical gases with antioxidant properties and discuss their clinical applications and therapeutic properties.

DOI： 10.3164/jcbn.08-193R

Experimental orthotopic lung transplantation model in rats with cold storage. Reviewed

Ryujiro Sugimoto, Atsunori Nakao, Itaru Nagahiro, Junichi Kohmoto, Seiichiro Sugimoto, Mikio Okazaki, Masaomi Yamane, Hidetoshi Inokawa, Takahiro Oto, Kazunori Tahara, Jianghua Zhan, Yoshifumi Sano, Kenneth R McCurry

Surgery today 39 ( 7 ) 641 - 5 2009

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

This report describes a new experimental procedure, a rat unilateral, orthotopic lung transplantation with cold storage, and evaluates its relevancy and reliability to study the early events during cold ischemia/reperfusion (I/R) injury. This model, using the cuff technique, does not require extensive training and is relatively easy to be established. The model can induce reproducible degrees of pulmonary graft injury including impaired gas exchange, proinflammatory cytokine upregulation, or inflammatory infiltrates, depending on the preservation time. The results are consistent with the previous clinical evidence, thus suggesting that this model is a valid and reliable animal model of cold I/R injury.

DOI： 10.1007/s00595-008-3929-x

Oral Administration of Hydrogen Water Prevents Chronic Allograft Nephropathy. Reviewed

Atsunori Nakao, Jianghua Zhan, Yinna Wang, Ryujiro Sugimoto, Jon Cardinal, Kenneth R. McCurry

AMERICAN JOURNAL OF TRANSPLANTATION 9 660 - 661 2009

Carbon monoxide-saturated preservation solution protects lung grafts from ischemia-reperfusion injury

Junichi Kohmoto, Atsunori Nakao, Ryujiro Sugimoto, Yinna Wang, JiangHua Zhan, Hideo Ueda, Kenneth R. McCurry

Journal of Thoracic and Cardiovascular Surgery 136 ( 4 ) 1067 - 1075 2008.10

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

Objectives: In previous work we have demonstrated that delivery of low concentrations (250 ppm) of carbon monoxide by means of inhalation to donors, recipients, or both protects transplanted lungs from ischemia-reperfusion injury (improved gas exchange, diminished intragraft and systemic inflammation, and retention of graft vascular endothelial cell ultrastructure). In this study we examined whether delivery of carbon monoxide to lung grafts in the preservation solution could protect against lung ischemia-reperfusion injury. Methods: Orthotopic left lung transplantation was performed in syngeneic Lewis to Lewis rats. Grafts were preserved in University of Wisconsin solution with or without (control solution) carbon monoxide at 4°C for 6 hours. Carbon monoxide gas (5% or 100%) was bubbled into University of Wisconsin solution at 4°C for 5 minutes before use. Results: In control animals, ischemia-reperfusion injury resulted in significant deterioration of graft function and was associated with a massive cellular infiltrate 2 hours after reperfusion. Grafts stored in University of Wisconsin solution with carbon monoxide (5%), however, demonstrated significantly better gas exchange and significantly reduced intragraft inflammation (reduced inflammatory mediators and cellular infiltrate). Experiments demonstrated that the protective effects afforded by 100% University of Wisconsin solution with carbon monoxide were not as potent as those of 5% University of Wisconsin solution with carbon monoxide. Conclusions: This study demonstrates that 5% carbon monoxide as an additive to the cold flush/preservation solution can impart potent anti-inflammatory and cytoprotective effects after cold preservation and transplantation of lung grafts. Such ex vivo treatment of lung grafts with carbon monoxide can minimize concerns associated with carbon monoxide inhalation and might offer the opportunity to significantly advance the application of carbon monoxide in the clinical setting. © 2008 The American Association for Thoracic Surgery.

DOI： 10.1016/j.jtcvs.2008.06.026

Ex vivo carbon monoxide prevents cytochrome P450 degradation and ischemia/reperfusion injury of kidney grafts. Reviewed International journal

Atsunori Nakao, Gaetano Faleo, Hiroko Shimizu, Kiichi Nakahira, Junichi Kohmoto, Ryujiro Sugimoto, Augustine M K Choi, Kenneth R McCurry, Toru Takahashi, Noriko Murase

Kidney international 74 ( 8 ) 1009 - 16 2008.10

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

Renal ischemia/reperfusion injury is a major complication of kidney transplantation. We tested if ex vivo delivery of carbon monoxide (CO) to the kidney would ameliorate the renal injury of cold storage that can complicate renal transplantation. Orthotopic syngeneic kidney transplantation was performed in Lewis rats following 24 h of cold preservation in University of Wisconsin solution equilibrated without or with CO (soluble CO levels about 40 microM). Ischemia/reperfusion injury in control grafts resulted in an early upregulation of inflammatory mediator mRNAs and progressive deterioration of graft function. In contrast, the grafts preserved with CO had significantly less oxidative injury and this was associated with improved recipient survival compared to the control group. Renal injury in the control group showed considerable degradation of cytochrome P450 heme proteins, active heme metabolism and increased detrimental intracellular free heme levels. Kidney grafts preserved in CO-equilibrated solution maintained their cytochrome P450 protein levels, had normal intracellular heme levels and had less lipid peroxidation. Our results show that CO-mediated suppression of injurious heme-derived redox reactions offers protection of kidney grafts from cold ischemia/reperfusion injury.

DOI： 10.1038/ki.2008.342

Sirolimus amelioration of clinical symptoms of recurrent lymphangioleiomyomatosis after living-donor lobar lung transplantation. Reviewed International journal

Ryujiro Sugimoto, Atsunori Nakao, Masaomi Yamane, Shinichi Toyooka, Megumi Okazaki, Motoi Aoe, Kuniaki Seyama, Hiroshi Date, Takahiro Oto, Yoshifumi Sano

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 27 ( 8 ) 921 - 4 2008.8

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

In this study we report the case of a 28-year-old female patient with recurrent lymphangioleiomyomatosis (LAM) in the allografts after bilateral living-donor lobar lung transplantation. Although her post-operative course under immunosuppression with tacrolimus and prednisolone had been uneventful without rejection episodes, she had developed shortness of breath and a progressive chylous effusion with diffuse cystic changes in both lungs 5 years after transplantation. In spite of a diagnosis of having a recurrence of LAM based on radiologic findings and deteriorating pulmonary function, her clinical symptoms, which included dyspnea and chylothorax, were significantly improved after treatment with sirolimus. Although a beneficial effect of sirolimus in the treatment of LAM has not been definitively determined, this report may provide useful information for management of recurrent LAM after lung transplantation.

DOI： 10.1016/j.healun.2008.05.012

Carbon monoxide ameliorates renal cold ischemia-reperfusion injury with an upregulation of vascular endothelial growth factor by activation of hypoxia-inducible factor. Reviewed International journal

Gaetano Faleo, Joao Seda Neto, Junichi Kohmoto, Koji Tomiyama, Hiroko Shimizu, Toru Takahashi, Yinna Wang, Ryujiro Sugimoto, Augustine M K Choi, Donna B Stolz, Giuseppe Carrieri, Kenneth R McCurry, Noriko Murase, Atsunori Nakao

Transplantation 85 ( 12 ) 1833 - 40 2008.6

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

BACKGROUND: We have previously shown that carbon monoxide (CO) inhalation at a low concentration provides protection against cold ischemia-reperfusion (I/R) injury after kidney transplantation. As vascular endothelial growth factor (VEGF) may promote the recovery process of impaired vascular endothelial cells during I/R injury, we examined whether protective effects of CO involved VEGF induction and its upstream hypoxia-inducible factor (HIF)-1 activation. METHODS: Lewis rat kidney graft, preserved in University of Wisconsin at 4 degrees C for 24 hr, was orthotopically transplanted into syngeneic recipient. Recipients were continuously maintained in air or exposed to CO (250 ppm) for 1 hr before and 24 hr after transplant. RESULTS: Prolonged cold preservation resulted in progressive impairment of kidney graft function with early inflammatory responses. Carbon monoxide significantly protected kidney grafts from cold I/R injury, improved renal function and enhanced recipient survival. Real-time reverse transcriptase-polymerase chain reaction revealed upregulation of HIF-1alpha and VEGF in the CO-treated kidney grafts as early as 1 hr after reperfusion. Western blot showed CO significantly upregulated VEGF expression 1 to 3 hr after kidney transplantation. Considerably more VEGF-positive cells were observed mainly in tubular epithelial cells in CO-treated, but not air-exposed, kidney grafts at 3 hr after reperfusion. YC-1, HIF-1alpha inhibitor, completely abrogated the actions of CO on VEGF induction and reversed the protective effects afforded by CO. Nitric oxide production in the grafts was increased by CO, however, abolished by YC-1. CONCLUSION: These results demonstrate that the protective effect of CO against renal cold I/R injury may involve VEGF upregulation through its upstream signal, HIF-1 activation.

DOI： 10.1097/TP.0b013e31817c6f63

The Oldest Patient with Gallstone Ileus: Report of a Case and Review of 176 Cases in Japan

NAKAO ATSUNORI, OKAMOTO YASUHISA, SUNAMI MASATAKA, FUJITA TAKUJI, TSUJI TAKAO

Kurume Med. J. 55 ( 1 ) 29 - 33 2008.5

Authorship：Lead author Language：English Publishing type：Research paper (bulletin of university, research institution) Publisher：Kurume University School of Medicine

We report a 91-year-old woman presenting bowel obstruction due to impacted gallstone, who was the oldest patient which has been reported in Japanese scientific literature. The patient was referred to our hospital due to vomiting and abdominal pain. Computed tomography and abdominal X-ray showed dilated loops of small intestine associated with air-fluid levels, pneumobilia, and a calcified mass in the left iliac fossa. After the diagnosis of bowel obstruction due to gallstone was made, an enterotomy and lithotomy was performed under spinal anesthesia. The postoperative recovery was uneventful. We also reviewed 176 cases of gallstone ileus which were reported in the Japanese literature in the past 20 years. The retrospective analysis demonstrated that one-stage enterolithotomy alone may be acceptable as the first choice of operative treatment. The gallstone ileus is a rare, but important disease because urgent and appropriate surgical therapy is required.

DOI： 10.2739/kurumemedj.55.29

Other Link： http://search.jamas.or.jp/link/ui/2009121716

Biliverdin-supplemented preservation solution attenuates cold ischemia/reperfusion injury of the lung Reviewed

Ryujiro Sugimoto, Atsunori Nakao, Gaetano Faleo, Yinna Wang, Timothy R. Billiar, Kenneth R. McCurry

AMERICAN JOURNAL OF TRANSPLANTATION 8 497 - 497 2008.5

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