Nilotinib protects the murine liver from ischemia/reperfusion injury
ABSTRACT 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.
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.
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.
Nilotinib lowers both liver JNK activation and NPC p38 MAPK activation and may be useful for ameliorating liver I/R injury in humans.
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ABSTRACT: Ischemia and reperfusion (I/R) injury is an often unavoidable consequence of major liver surgery and is characterized by a sterile inflammatory response that jeopardizes the viability of the organ. The inflammatory response results from acute oxidative and nitrosative stress and consequent hepatocellular death during the early reperfusion phase, which causes the release of endogenous self-antigens known as damage-associated molecular patterns (DAMPs). DAMPs in turn initiate a second wave of reactive oxygen and nitrogen species (ROS and RNS) production by driving the chemoattraction of various leukocyte subsets that exacerbate liver damage during the later stages of reperfusion. In this review, the molecular mechanisms underlying hepatic I/R injury are outlined, with emphasis on the interplay between ROS/RNS, DAMPs, and the cell types that either produce ROS/RNS and DAMPs or respond to them. This theoretical background is subsequently used to explain why current interventions for hepatic I/R injury have not been successful. Moreover, novel therapeutic modalities are addressed, including MitoSNO and nilotinib, on the basis of the updated paradigm of hepatic I/R injury.Journal of Gastroenterology and Hepatology 12/2012; 28(3). DOI:10.1111/jgh.12072 · 3.50 Impact Factor
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ABSTRACT: Tumor necrosis factor-α (TNF-α) is a potent proinflammatory cytokine involved in a variety of disease pathologies, including ischemia/reperfusion (I/R) injuries in transplantation. The interaction of TNF-α with its cognate receptor TNF receptor I (TNFRI) results in the activation of signal transduction pathways that regulate either cell survival or cell death. Hepatocytes express TNFRI and respond to TNF-α released by resident Kupffer cells as well as leukocytes that migrate to the liver during I/R injury. Upon binding TNF-α, the hepatocyte proliferates or undergoes apoptosis or necroptosis. The decision by the cell to commit to one path or the other is not understood. The damaged tissue exhibits cell death and hemorrhaging from the influx of immune mediators. TNF-α inhibitors ameliorate the injury in animal models, suggesting that lowering (but not eliminating) TNF-α levels shifts the balance of TNF-α toward its beneficial functions. We review TNF-α signal transduction pathways and the role of TNF-α in liver I/R injury. Because TNF-α plays an important role in hepatocyte proliferation, complete inhibition of TNF-α is not desirable in treating liver I/R injury. The strategy for developing pharmacological therapies may be the identification of specific intermediates in the TNF-α/TNFR1 signal transduction pathway and directed targeting of proapoptotic and pronecroptotic events.Ochsner Journal 03/2013; 13(1):119-30.
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ABSTRACT: Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction post-transplantation. Cellular and biochemical processes occurring during hepatic ischemia-reperfusion are diverse and complex, and include the de-regulation of the healthy phenotype of all liver cellular components. Nevertheless, a significant part of these processes are still unknown or unclear. The present review aims to summarize the current knowledge in liver ischemia-reperfusion but specifically focusing on liver cells phenotype and paracrine interactions de-regulations. Moreover, the most updated therapeutic strategies including pharmacological, genetic and surgical interventions, as well as some of the scientific controversies in the field will be described. Finally, the importance of considering the subclinical situation of liver grafts when translating basic knowledge to the bedside is discussed.Journal of Hepatology 06/2013; 125(5). DOI:10.1016/j.jhep.2013.06.017 · 11.34 Impact Factor