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  • Title: Reperfusion after liver transplantation in rats differentially activates the mitogen-activated protein kinases.
    Author: Bradham CA, Stachlewitz RF, Gao W, Qian T, Jayadev S, Jenkins G, Hannun Y, Lemasters JJ, Thurman RG, Brenner DA.
    Journal: Hepatology; 1997 May; 25(5):1128-35. PubMed ID: 9141429.
    Abstract:
    The injury resulting from cold ischemia and warm reperfusion during liver transplantation is a major clinical problem that limits graft success. Kupffer cell activation plays a pivotal role in reperfusion injury, and Kupffer cell products, including free radicals and tumor necrosis factor alpha (TNF-alpha), are implicated as damaging agents. However, the second messengers and signaling pathways that are activated by the stress of hepatic ischemia/reperfusion remain unknown. The purpose of this study is to assess the activation of the three known vertebrate mitogen activated protein kinase (MAPKs) and the activating protein 1 (AP-1) transcription factor in response to ischemia and reperfusion in the transplanted rat liver. There was a potent, sustained induction of c-jun N-terminal kinase (JNK), but not of the related MAPKs extracellular signal-regulated kinases (ERK) or p38, upon reperfusion after transplantation. TNF-alpha messenger RNA (mRNA) levels and transcription factors AP-1 and nuclear factor-kappaB (NF-kappaB) were induced in the liver after 60 minutes of reperfusion. Finally, there was an elevation of ceramide, but not diacylglycerol or sphingosine, in the transplanted liver. Ceramide is a second messenger generated by TNF-alpha treatment and is an activator of JNK. Because JNK activation preceded the elevations in ceramide and TNF-alpha mRNA, these results suggest that increased hepatic TNF-alpha and ceramide may perpetuate JNK induction, but that they are not the initiating signals of JNK activation during reperfusion injury in the transplanted liver.
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