Faculty Profiles - MATSUKAWA Akihiro

Papers - MATSUKAWA Akihiro

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Aberrant inflammation and lethality to septic peritonitis in mice lacking STAT3 in macrophages and neutrophils Reviewed International journal

A Matsukawa, K Takeda, S Kudo, T Maeda, M Kagayama, S Akira

JOURNAL OF IMMUNOLOGY 171 ( 11 ) 6198 - 6205 2003.12

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.

Detection of neutrophils and possible involvement of interleukin-8 in diffuse lamellar keratitis after laser in situ keratomileusis Reviewed International journal

N Asano-Kato, Toda, I, S Shimmura, T Noda-Tsuruya, K Fukagawa, M Yoshinaga, A Matsukawa, K Tsubota

JOURNAL OF CATARACT AND REFRACTIVE SURGERY 29 ( 10 ) 1996 - 2000 2003.10

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

Tumor necrosis factor-a inhibition reduces CXCL-8 levels but fails to prevent fibrin generation and does not improve outcome in a rabbit model of endotoxic shock Reviewed International journal

P Rodriguez-Wilhelmi, R Montes, A Matsukawa, H Nariuchi, Hurtado, V, M Montes, J Hermida, E Rocha

JOURNAL OF LABORATORY AND CLINICAL MEDICINE 141 ( 4 ) 257 - 264 2003.4

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

Chemokines in granulomatous lung inflammation

Stephen W. Chensue, Akihiro Matsukawa, Cory M. Hogaboam, Steven L. Kunkel

Chemokines in the Lung 221 - 237 2003.1

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.

Regulation of innate immune response by Stat proteins during septic peritonitis ; in The biological response to planned and unplanned injuries : Cellular, molecular and genetic aspects Invited Reviewed

MATSUKAWA A

Excerpta Medica International Congress Series 1255 7 - 14 2003

Interleukin (IL)-8 and growth related oncogene-alpha in severe endotoxemia and the effects of a tumor necrosis factor-alpha/IL-1 beta inhibitor on these chemokines Reviewed International journal

P Rodriguez-Wilhelmi, R Montes, A Matsukawa, Hurtado, V, M Montes, J Hermida, E Rocha

EXPERIMENTAL AND MOLECULAR PATHOLOGY 73 ( 3 ) 220 - 229 2002.12

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

Expression of monocyte chemoattractant protein-1 in primary cultures of rabbit intervertebral disc cells Reviewed International journal

M Yoshida, T Nakamura, T Kikuchi, K Takagi, A Matsukawa

JOURNAL OF ORTHOPAEDIC RESEARCH 20 ( 6 ) 1298 - 1304 2002.11

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

The endotoxin-induced plasminogen activator inhibitor-1 increase in rabbits is not tumor necrosis factor-alpha dependent and can occur in the absence of interleukin-1 beta Reviewed International journal

R Montes, P Rodriguez-Whilhelmi, Hurtado, V, A Matsukawa, M Montes, J Hermida, E Rocha

THROMBOSIS AND HAEMOSTASIS 88 ( 4 ) 639 - 643 2002.10

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.

Involvement of CXC chemokine growth-related oncogene-alpha in monosodium urate crystal-induced arthritis in rabbits Reviewed International journal

K Fujiwara, S Ohkawara, K Takagi, M Yoshinaga, A Matsukawa

LABORATORY INVESTIGATION 82 ( 10 ) 1297 - 1304 2002.10

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

Mice genetically lacking endothelial selectins are resistant to the lethality in septic peritonitis Reviewed International journal

A Matsukawa, NW Lukacs, CM Hogaboam, RN Knibbs, DC Bullard, SL Kunkel, LM Stoolman

EXPERIMENTAL AND MOLECULAR PATHOLOGY 72 ( 1 ) 68 - 76 2002.2

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

Local overexpression of monocyte chemoattractant protein-1 at vessel wall induces infiltration of macrophages and formation of atherosclerotic lesion - Synergism with hypercholesterolemia Reviewed International journal

M Namiki, S Kawashima, T Yamashita, M Ozaki, T Hirase, T Ishida, N Inoue, K Hirata, A Matsukawa, R Morishita, Y Kaneda, M Yokoyama

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 22 ( 1 ) 115 - 120 2002.1

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

Functional distinction between CXC chemokines, interleukin-8 (IL-8), and growth related oncogene (GRO)alpha in neutrophil infiltration Reviewed International journal

K Fujiwara, A Matsukawa, S Ohkawara, K Takagi, M Yoshinaga

LABORATORY INVESTIGATION 82 ( 1 ) 15 - 23 2002.1

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.

Effect of methylprednisolone on phospholipase A(2) activity and lung surfactant degradation in acute lung injury in rabbits Reviewed

K Kuwabara, S Furue, Y Tomita, M Ueno, T Ono, A Matsukawa, M Yoshinaga, K Mikawa, K Nishina, M Shiga, H Obara, Y Hori

EUROPEAN JOURNAL OF PHARMACOLOGY 433 ( 2-3 ) 209 - 216 2001.12

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

Interleukin-1 beta in antigen-induced arthritis of the rabbit temporomandibular joint Reviewed

K Tominaga, P Alstergren, H Kurita, A Matsukawa, J Fukuda, S Kopp

ARCHIVES OF ORAL BIOLOGY 46 ( 6 ) 539 - 544 2001.6

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

III. Chemokines and other mediators, 8. Chemokines and their receptors in cell-mediated immune responses in the lung Invited Reviewed

A Matsukawa, NW Lukacs, CM Hogaboam, SW Chensue, SL Kunkel

MICROSCOPY RESEARCH AND TECHNIQUE 53 ( 4 ) 298 - 306 2001.5

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

Therapeutic time-window of a group IIA phospholipase A(2) inhibitor in rabbit acute lung injury: Correlation with lung surfactant protection Reviewed

S Furue, K Mikawa, K Nishina, M Shiga, M Ueno, Y Tomita, K Kuwabara, Teshirogi, I, T Ono, Y Hori, A Matsukawa, M Yoshinaga, H Obara

CRITICAL CARE MEDICINE 29 ( 4 ) 719 - 727 2001.4

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.

Erythromycin attenuates an experimental model of chronic bronchiolitis via augmenting monocyte chemoattractant protein-1 Reviewed

T Takahashi, M Suga, A Matsukawa, K Sato, T Okamoto, H Ichiyasu, S Ohkawara, M Yoshinaga, M Ando

EUROPEAN RESPIRATORY JOURNAL 17 ( 3 ) 360 - 367 2001.3

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

Pivotal role of signal transducer and activator of transcription (Stat)4 and Stat6 in the innate immune response during sepsis Reviewed

A Matsukawa, MH Kaplan, CM Hogaboam, NW Lukacs, SL Kunkel

JOURNAL OF EXPERIMENTAL MEDICINE 193 ( 6 ) 679 - 688 2001.3

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

Early recruitment of neutrophils determines subsequent T1/T2 host responses in a murine model of Legionella pneumophila pneumonia Reviewed

K Tateda, TA Moore, JC Deng, MW Newstead, XY Zeng, A Matsukawa, MS Swanson, K Yamaguchi, TJ Standiford

JOURNAL OF IMMUNOLOGY 166 ( 5 ) 3355 - 3361 2001.3

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.

緑膿菌誘発家兎びまん性汎細気管支炎におけるエリスロマイシンの効果-MCP-1産生増加による肉芽腫様病変の改善

高橋利弘, 菅守隆, 佐藤圭創, 岡本龍哉, 一安秀範, 松川昭博, 大河原進, 吉永秀, 安藤正幸

Jpn. J. Antibiot 54 ( 増刊A ) 125 - 129 2001

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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