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
StatePublished - Oct 1 2012
Externally publishedYes

Fingerprint

Reperfusion Injury
Liver
p38 Mitogen-Activated Protein Kinases
Phosphotransferases
Receptor Protein-Tyrosine Kinases
Cytokines
Mitogen-Activated Protein Kinases
Hepatocytes
Interleukin-6
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
Apoptosis
JNK Mitogen-Activated Protein Kinases
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Serum
Interleukin-1
Monocytes
Histology
Flow Cytometry
Cell Death
Western Blotting

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

Nilotinib protects the murine liver from ischemia/reperfusion injury. / Ocuin, Lee M.; Zeng, Shan; Cavnar, Michael J.; Sorenson, Eric C.; Bamboat, Zubin M.; Greer, Jonathan; Kim, Teresa S.; Popow, Rachel; Dematteo, Ronald P.

In: Journal of Hepatology, Vol. 57, No. 4, 01.10.2012, p. 766-773.

Research output: Contribution to journalArticle

Ocuin, LM, Zeng, S, Cavnar, MJ, Sorenson, EC, Bamboat, ZM, Greer, J, Kim, TS, Popow, R & Dematteo, RP 2012, 'Nilotinib protects the murine liver from ischemia/reperfusion injury', Journal of Hepatology, vol. 57, no. 4, pp. 766-773. https://doi.org/10.1016/j.jhep.2012.05.012
Ocuin, Lee M. ; Zeng, Shan ; Cavnar, Michael J. ; Sorenson, Eric C. ; Bamboat, Zubin M. ; Greer, Jonathan ; Kim, Teresa S. ; Popow, Rachel ; Dematteo, Ronald P. / Nilotinib protects the murine liver from ischemia/reperfusion injury. In: Journal of Hepatology. 2012 ; Vol. 57, No. 4. pp. 766-773.
@article{408355d6ddca46429cd97b09192cf242,
title = "Nilotinib protects the murine liver from ischemia/reperfusion injury",
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.",
keywords = "c-Jun NH-terminal kinase, Cytokines, Hepatocytes, Non-parenchymal cells, p38 MAPK",
author = "Ocuin, {Lee M.} and Shan Zeng and Cavnar, {Michael J.} and Sorenson, {Eric C.} and Bamboat, {Zubin M.} and Jonathan Greer and Kim, {Teresa S.} and Rachel Popow and Dematteo, {Ronald P.}",
year = "2012",
month = "10",
day = "1",
doi = "10.1016/j.jhep.2012.05.012",
language = "English (US)",
volume = "57",
pages = "766--773",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier",
number = "4",

}

TY - JOUR

T1 - Nilotinib protects the murine liver from ischemia/reperfusion injury

AU - Ocuin, Lee M.

AU - Zeng, Shan

AU - Cavnar, Michael J.

AU - Sorenson, Eric C.

AU - Bamboat, Zubin M.

AU - Greer, Jonathan

AU - Kim, Teresa S.

AU - Popow, Rachel

AU - Dematteo, Ronald P.

PY - 2012/10/1

Y1 - 2012/10/1

N2 - 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.

AB - 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.

KW - c-Jun NH-terminal kinase

KW - Cytokines

KW - Hepatocytes

KW - Non-parenchymal cells

KW - p38 MAPK

UR - http://www.scopus.com/inward/record.url?scp=84866385959&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866385959&partnerID=8YFLogxK

U2 - 10.1016/j.jhep.2012.05.012

DO - 10.1016/j.jhep.2012.05.012

M3 - Article

VL - 57

SP - 766

EP - 773

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

IS - 4

ER -