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Use of a Hanging-weight System for Liver Ischemia in Mice
Published on: August 7, 2012
Nilotinib protects the murine liver from ischemia/reperfusion injury
Lee M Ocuin1, Shan Zeng, Michael J Cavnar
1Hepatopancreatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Background & Aims:
The 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.
Methods:
The 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.
Results:
Mice 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.
Conclusions:
Nilotinib lowers both liver JNK activation and NPC p38 MAPK activation and may be useful for ameliorating liver I/R injury in humans.
Insights
Nilotinib reduces liver injury and apoptosis in a mouse model of ischemia/reperfusion (I/R) by inhibiting c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs). This suggests nilotinib may treat hepatic I/R injury.
Area of Science:
- Hepatology
- Pharmacology
- Immunology
Background:
- Liver ischemia/reperfusion (I/R) injury involves cell death and inflammation mediated by mitogen-activated protein kinases (MAPKs), specifically c-Jun N-terminal kinase (JNK) and p38.
- Nilotinib, a tyrosine kinase inhibitor, shows in vitro activity against JNK and p38, indicating potential therapeutic applications.
Purpose of the Study:
- To investigate the therapeutic potential of nilotinib in mitigating liver ischemia/reperfusion (I/R) injury.
- To examine nilotinib's effects on MAPK activation, cytokine production, and cell death in hepatic I/R.
Main Methods:
- A murine model of warm, segmental liver I/R was used to assess nilotinib's effects.
- Analyses included serum ALT levels, liver histology, RT-PCR, Western blot, flow cytometry, and in vitro testing on hepatocytes and non-parenchymal cells (NPCs).
Main Results:
- Nilotinib treatment significantly reduced serum ALT levels, histologic injury, and apoptosis in mice subjected to liver I/R.
- Nilotinib suppressed intrahepatic and systemic inflammatory cytokine expression (IL-1β, IL-6, MCP-1, MIP-2, TNF) and reduced NPC activation of p38 MAPK.
- The drug attenuated JNK phosphorylation in hepatocytes and p38 MAPK activation in NPCs, decreasing inflammatory monocyte recruitment and TNF production.
Conclusions:
- Nilotinib effectively ameliorates liver I/R injury by inhibiting both hepatocyte JNK activation and NPC p38 MAPK activation.
- These findings suggest nilotinib holds promise as a therapeutic agent for treating liver I/R injury in humans.
