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- Title
p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation
- Authors
Gao, Feng; Yue, Tian-Li; Shi, Dong-Wei; Christopher, Theodore A.; Lopez, Bernard L.; Ohlstein, Eliot H.; Barone, Frank C.; Ma, Xin L.
- Abstract
<B>Background:</B> 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. <B>Methods and results:</B> 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. <B>Conclusion:</B> 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.
- Subjects
PROTEIN kinases; INFLAMMATION; ISCHEMIA; MYOCARDIAL infarction; REPERFUSION injury
- Publication
Cardiovascular Research, 2002, Vol 53, Issue 2, p414
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1016/S0008-6363(01)00488-6