P38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation

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 studs, 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 239003 significantly attenuated I/R-induced P-selectin and ICAM-I 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 CID 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. (C) 2002 Published by Elsevier Science B.V.