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Reperfusion after liver transplantation in rats differentially activates the mitogen‐activated protein kinases
Author(s) -
Bradham C A,
Stachlewitz R F,
Gao W,
Qian T,
Jayadev S,
Jenkins G,
Hannun Y,
Lemasters J J,
Thurman R G,
Brenner D A
Publication year - 1997
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510250514
Subject(s) - ceramide , kinase , mapk/erk pathway , mitogen activated protein kinase , p38 mitogen activated protein kinases , reperfusion injury , kupffer cell , biology , transplantation , liver transplantation , microbiology and biotechnology , medicine , endocrinology , immunology , ischemia , biochemistry , apoptosis
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 α (TNF‐α), 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‐α messenger RNA (mRNA) levels and transcription factors AP‐1 and nuclear factor‐κB (NF‐κB) 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‐α treatment and is an activator of JNK. Because JNK activation preceded the elevations in ceramide and TNF‐α mRNA, these results suggest that increased hepatic TNF‐α and ceramide may perpetuate JNK induction, but that they are not the initiating signals of JNK activation during reperfusion injury in the transplanted liver.