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

Sotraustaurin (STN), a small molecule, targeted protein kinase C (PKC) inhibitor that prevents Tlymphocyte 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-jB/ERK signaling, depressed proapoptotic cleaved caspase-3, yet upregulated antiapoptotic Bcl-2/Bcl-xl and hepatic cell proliferation. In vitro, STN decreased PKCh/IjBa activation and IL-2/IFN-c production in ConA-stimulated spleen T cells, and diminished TNF-a /IL-1b in macrophage-T cell cocultures. This study documents positive effects of STN on liver IRI in OLT ratmodel thatmay translate as an additional benefit of STN in clinical liver transplantation.