title: 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.
authors: Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors: N
authors: N
authors: Kamo
authors: X-D
authors: XD
authors: Shen
authors: B
authors: B
authors: Ke
authors: R W
authors: RW
authors: Busuttil
authors: J W
authors: JW
authors: Kupiec-Weglinski
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050377:Cold Ischemia; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D022781:Hepatocytes / Q000502:physiology; D016031:Liver Transplantation / Q000473:pathology / Q000502:physiology*; D008297:Male; D016328:NF-kappa B / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology
chemical_list: D016328:NF-kappa B; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases