کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
6106320 1211160 2012 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Research ArticleNilotinib protects the murine liver from ischemia/reperfusion injury
موضوعات مرتبط
علوم پزشکی و سلامت پزشکی و دندانپزشکی بیماری‌های گوارشی
پیش نمایش صفحه اول مقاله
Research ArticleNilotinib protects the murine liver from ischemia/reperfusion injury
چکیده انگلیسی

Background & aimsThe mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK), and p38, mediate liver ischemia/reperfusion (I/R) injury via cell death and inflammatory cytokine expression, respectively. Nilotinib is an orally available receptor tyrosine kinase inhibitor used for chronic myelogenous leukemia that also has in vitro activity against JNK and p38. In this study, we examine its therapeutic potential against hepatic I/R injury.MethodsThe effects of nilotinib on liver I/R injury were tested using a murine model of warm, segmental liver I/R. Serum ALT was measured and livers were analyzed by histology, RT-PCR, Western blot, and flow cytometry. The in vitro effects of nilotinib on hepatocyte and non-parenchymal cell (NPC) MAPK activation and cytokine production were also tested.ResultsMice receiving nilotinib had markedly lower serum ALT levels and less histologic injury and apoptosis following liver I/R. Nilotinib did not inhibit its known receptor tyrosine kinases. Nilotinib lowered intrahepatic expression of IL-1β, IL-6, MCP-1, and MIP-2 and systemic levels of IL-6, MCP-1, and TNF. Nilotinib reduced NPC activation of p38 MAPK signaling and decreased the recruitment of inflammatory monocytes and their production of TNF. Nilotinib attenuated JNK phosphorylation and hepatocellular apoptosis. In vitro, nilotinib demonstrated direct inhibition of JNK activation in isolated hepatocytes cultured under hypoxic conditions, and blocked activation of p38 MAPK and cytokine production by stimulated NPCs.ConclusionsNilotinib lowers both liver JNK activation and NPC p38 MAPK activation and may be useful for ameliorating liver I/R injury in humans.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Hepatology - Volume 57, Issue 4, October 2012, Pages 766-773
نویسندگان
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