Sotrastaurin, a Protein Kinase C Inhibitor, Ameliorates Ischemia and Reperfusion Injury in Rat Orthotopic Liver Transplantation

Authors

  • N. Kamo,

    1. Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA
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  • X.-D. Shen,

    1. Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA
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  • B. Ke,

    1. Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA
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  • R. W. Busuttil,

    1. Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA
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  • J. W. Kupiec-Weglinski

    Corresponding author
    1. Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA
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Jerzy W. Kupiec-Weglinski, jkupiec@mednet.ucla.edu

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.

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