© 2002 by European Society of Cardiology
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
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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