The role of MARK in hepatic ischemia-reperfusion injury

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Patients with end-stage liver disease in Japan still depend on living-donor liver transplantation, since cadaveric organ donation is extremely rare. Because ischemia-reperfusion injury of the graft organ is inevitable in transplantation, control of ischemic injury enable us to use the organ safely from unsalable or nonheartbeating donor, leading to the improvement of organ shortage. We have been demonstrated the key role of tumor necrosis factor (TNF) and interleukin-1 in ischemia-reperfusion injury of the liver and small intestine. Recently, mitogen-activated protein kinase (MAPK) super family has been widely noticed as upupstream signal transduction mechanisms for TNF-α and IL-1β have been reported. Especially, c-Jun N-terminal kinase (JNK) induce cell apoptosis by various stimuli including ischemia, suggesting these enzymes play a key role in ischemia reperfusion injury. We investigated the activation of JNK during hepatic ischemia-reperfusion injury in the rat model.Remarkable hemrrahgic necrosis was shown in the reperfused liver after 60-minute warm ischemia, and the mean serum AST increased over 2000 IU/L at 180 minutes after reperfusion, indicating that severe liver damage was induced. In vivo microfluorograph showed remarkable increase in leukocyte-endothelium interaction in sinusoids and venules of the reperfused liver. After reperfusion, tissue and serum TNF-α level increased over 6 folds, and tissue JNK activity increased by 12.5 folds, compared to the value before ischemia. These results suggest that JNK may play some role in the mechnism of ischemia reperfusion injury.