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Cardiovascular Research 2002 53(2):414-422; doi:10.1016/S0008-6363(01)00488-6
© 2002 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation

Feng Gaoa,1, Tian-Li Yueb,1, Dong-Wei Shia, Theodore A Christophera, Bernard L Lopeza, Eliot H Ohlsteinb, Frank C Baroneb and Xin L Maa,*

aDivision of Emergency Medicine, Jefferson Medical College, Thomas Jefferson University, 1020 Sansom Street, Philadelphia, PA 19107-5004, USA
bDepartment of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA, USA

* Corresponding author. Tel.: +1-215-955-4994; fax: +1-215-923-6225 xin.ma{at}mail.tju.edu

Background: In vitro evidence suggests that the p38 mitogen-activated protein kinase (p38 MAPK) plays a crucial role in PMN activation and inflammatory cytokine production. However, the effect of p38 MAPK on myocardial reperfusion injury, a pathologic condition involving a typical inflammatory response, has not been fully examined. In the present study, we investigated the effect of SB 239063, a specific p38 MAPK inhibitor, on myocardial injury in a murine ischemia/reperfusion (I/R) model and elucidated the mechanism by which p38 MAPK inhibitor may exert its protective effect against I/R injury. Methods and results: I/R resulted in a significant myocardial injury (myocardial infarct 45±2.9%) and marked PMN accumulation (myeloperoxidase activity 1.03±0.16 U/100 g tissue). Administration of SB 239063 significantly inhibited the myocardial inflammatory response as evidenced by reduced PMN accumulation in I/R myocardial tissue (0.62±0.008 U/100 g tissue, P<0.01 vs. vehicle), and markedly attenuated myocardial reperfusion injury (myocardial infarct size: 28±2.4%, P<0.01 vs. vehicle). Moreover, treatment with SB 239063 significantly attenuated I/R-induced P-selectin and ICAM-1 upregulation (13.8±2.7 vs. 23.9±3.1%, and 29.4±1.6 vs. 56.3±4.8%, respectively P<0.01). In addition, pre-treatment with R15.7, a monoclonal antibody against CD 18 adhesion molecule on PMN surface that virtually abolished PMN accumulation in ischemic-reperfused myocardial tissue, significantly, but not completely, blocked the cardioprotection exerted by SB 239063. Conclusion: These results demonstrated for the first time that p38 MAPK activation plays a significant role in adhesion molecule upregulation on ischemia-reperfused endothelial cells and is an important signaling step in the pathogenesis of PMN-mediated tissue injury.

KEYWORDS Infection/inflammation; Ischemia; Reperfusion; Signal transduction


1 The first two authors made an equal contribution to this study.


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