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Sotrastaurin, a protein kinase C inhibitor, ameliorates ischemia and reperfusion injury in rat orthotopic liver transplantation.

Abstract
Sotraustaurin (STN), a small molecule, targeted protein kinase C (PKC) inhibitor that prevents T-lymphocyte activation via a calcineurin-independent pathway, is currently being tested in Phase II renal and liver transplantation clinical trials. We have documented the key role of activated T cells in the inflammation cascade leading to liver ischemia/reperfusion injury (IRI). This study explores putative cytoprotective functions of STN in a clinically relevant rat model of hepatic cold ischemia followed by orthotopic liver transplantation (OLT). Livers from Sprague-Dawley rats were stored for 30 h at 4°C in UW solution, and then transplanted to syngeneic recipients. STN treatment of liver donors/recipients or recipients only prolonged OLT survival to >90% (vs. 40% in controls), decreased hepatocellular damage and improved histological features of IRI. STN treatment decreased activation of T cells, and diminished macrophage/neutrophil accumulation in OLTs. These beneficial effects were accompanied by diminished apoptosis, NF-κB/ERK signaling, depressed proapoptotic cleaved caspase-3, yet upregulated antiapoptotic Bcl-2/Bcl-xl and hepatic cell proliferation. In vitro, STN decreased PKCθ/IκBα activation and IL-2/IFN-γ production in ConA-stimulated spleen T cells, and diminished TNF-α/IL-1β in macrophage-T cell cocultures. This study documents positive effects of STN on liver IRI in OLT rat model that may translate as an additional benefit of STN in clinical liver transplantation.
AuthorsN Kamo, X-D Shen, B Ke, R W Busuttil, J W Kupiec-Weglinski
JournalAmerican journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (Am J Transplant) Vol. 11 Issue 11 Pg. 2499-507 (Nov 2011) ISSN: 1600-6143 [Electronic] United States
PMID21883905 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Copyright©2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.
Chemical References
  • NF-kappa B
  • Pyrroles
  • Quinazolines
  • sotrastaurin
  • Protein Kinase C
  • Extracellular Signal-Regulated MAP Kinases
Topics
  • Animals
  • Apoptosis (drug effects)
  • Cell Proliferation (drug effects)
  • Cold Ischemia
  • Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors)
  • Hepatocytes (physiology)
  • Liver Transplantation (pathology, physiology)
  • Male
  • NF-kappa B (physiology)
  • Protein Kinase C (antagonists & inhibitors)
  • Pyrroles (therapeutic use)
  • Quinazolines (therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury (prevention & control)
  • Signal Transduction (drug effects)
  • T-Lymphocytes (drug effects, physiology)

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