Nilotinib protects the murine liver from ischemia/reperfusion injury

Lee M. Ocuin, Shan Zeng, Michael J. Cavnar, Eric C. Sorenson, Zubin M. Bamboat, Jonathan Greer, Teresa S. Kim, Rachel Popow, Ronald P. Dematteo

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)766-773
Number of pages8
JournalJournal of Hepatology
Volume57
Issue number4
DOIs
Publication statusPublished - Oct 1 2012
Externally publishedYes

    Fingerprint

Keywords

  • c-Jun NH-terminal kinase
  • Cytokines
  • Hepatocytes
  • Non-parenchymal cells
  • p38 MAPK

ASJC Scopus subject areas

  • Hepatology

Cite this

Ocuin, L. M., Zeng, S., Cavnar, M. J., Sorenson, E. C., Bamboat, Z. M., Greer, J., ... Dematteo, R. P. (2012). Nilotinib protects the murine liver from ischemia/reperfusion injury. Journal of Hepatology, 57(4), 766-773. https://doi.org/10.1016/j.jhep.2012.05.012