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

doi:10.1016/S0008-6363(01)00488-6

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

Feng Gao^a^,1, Tian-Li Yue^b^,1, Dong-Wei Shi^a, Theodore A Christopher^a, Bernard L Lopez^a, Eliot H Ohlstein^b, Frank C Barone^b and Xin L Ma^a^,*

^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-activatedprotein kinase (p38 MAPK) plays a crucial role in PMN activationand inflammatory cytokine production. However, the effect ofp38 MAPK on myocardial reperfusion injury, a pathologic conditioninvolving a typical inflammatory response, has not been fullyexamined. In the present study, we investigated the effect ofSB 239063, a specific p38 MAPK inhibitor, on myocardial injuryin a murine ischemia/reperfusion (I/R) model and elucidatedthe mechanism by which p38 MAPK inhibitor may exert its protectiveeffect against I/R injury. Methods and results: I/R resultedin a significant myocardial injury (myocardial infarct 45±2.9%)and marked PMN accumulation (myeloperoxidase activity 1.03±0.16U/100 g tissue). Administration of SB 239063 significantly inhibitedthe myocardial inflammatory response as evidenced by reducedPMN accumulation in I/R myocardial tissue (0.62±0.008U/100 g tissue, P<0.01 vs. vehicle), and markedly attenuatedmyocardial reperfusion injury (myocardial infarct size: 28±2.4%,P<0.01 vs. vehicle). Moreover, treatment with SB 239063 significantlyattenuated I/R-induced P-selectin and ICAM-1 upregulation (13.8±2.7vs. 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 PMNsurface that virtually abolished PMN accumulation in ischemic-reperfusedmyocardial tissue, significantly, but not completely, blockedthe cardioprotection exerted by SB 239063. Conclusion: Theseresults demonstrated for the first time that p38 MAPK activationplays a significant role in adhesion molecule upregulation onischemia-reperfused endothelial cells and is an important signalingstep 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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