The caspase inhibitor IDN-6556 prevents caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury
Open Access
- 1 March 2003
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Liver Transplantation
- Vol. 9 (3), 278-284
- https://doi.org/10.1053/jlts.2003.50019
Abstract
Cold ischemia (CI)–warm reperfusion (WR) liver injury remains a problem in liver transplantation. CI‐WR initially causes sinusoidal endothelial cell (SEC) apoptosis through a caspase‐dependent mechanism. We previously showed that the caspase inhibitor IDN‐1965 prevents CI‐WR–induced SEC apoptosis. However, this agent required to be administered to the donor, preservation solution, and recipient for efficacy. Here, we show that a second‐generation caspase inhibitor, IDN‐6556, effectively prevents CI‐WR–induced SEC injury when added only to University of Wisconsin (UW) cold storage media. Rat livers were stored in UW solution for 24 hours at 4°C and reperfused for 1 hour at 37°C. Apoptosis was quantitated using terminal deoxynucleotide transferasemediated deoxyuridine triphosphate nick end labeling (TUNEL) assay and caspase 3 activation determined by biochemical measurement and immunohistochemical analysis. Pan‐caspase inhibitors (IDN‐8066, IDN‐7503, IDN‐7436, IDN‐1965, and IDN‐6556) were applied at preischemic, cold preservation, or reperfusion periods. TUNEL‐positive SEC and caspase 3–like activity in the liver was increased by CI‐WR. Three caspase inhibitors (IDN‐8066, IDN‐1965, and IDN‐6556) effectively attenuated SEC apoptosis and caspase 3 activation. The most potent inhibitor, IDN‐6556, reduced SEC apoptosis and caspase 3 activity by 55% and 94%, respectively. Prevention of SEC apoptosis by IDN‐6556 was not reduced when this agent was administered only during the cold preservation period. When added to the preservation solution, the caspase inhibitor IDN‐6556 appears to be a feasible therapeutic agent against ischemia‐reperfusion injury in liver transplantation.Keywords
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