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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Authors | N Kamo, X-D Shen, B Ke, R W Busuttil, J W Kupiec-Weglinski |
Journal | American 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 |
PMID | 21883905
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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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
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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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