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 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.


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.


CONCLUSIONS
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.
Gao
Feng
F
Division of Emergency Medicine, Jefferson Medical College, Thomas Jefferson University, 1020 Sansom Street, Philadelphia, PA 19107-5004, USA.
Yue
Tian-Li
TL
Shi
Dong-Wei
DW
Christopher
Theodore A
TA
Lopez
Bernard L
BL
Ohlstein
Eliot H
EH
Barone
Frank C
FC
Ma
Xin L
XL
D000704:Analysis of Variance; D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000037:antagonists & inhibitors*; D009203:Myocardial Infarction / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000517:prevention & control*; D009504:Neutrophils / Q000502:physiology; D019007:P-Selectin / Q000032:analysis; D009195:Peroxidase / Q000032:analysis; D011743:Pyrimidines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases
D007093:Imidazoles; D019007:P-Selectin; D011743:Pyrimidines; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063