The caspase inhibitor IDN-6556 prevents caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury.

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 degrees C and reperfused for 1 hour at 37 degrees 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.

• Authors: Shiho Natori, Hajime Higuchi, Patricia Contreras, Gregory J Gores
• Journal: Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society (Liver Transpl) Vol. 9 Issue 3 Pg. 278-84 (Mar 2003) ISSN: 1527-6465 [Print] United States
• PMID: 12619025 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Caspase Inhibitors
• Enzyme Inhibitors
• Insulin
• Organ Preservation Solutions
• University of Wisconsin-lactobionate solution
• Allopurinol
• Casp3 protein, rat
• Caspase 3
• Caspases
• Glutathione
• Adenosine
• Raffinose

Topics

• Adenosine (pharmacology)
• Allopurinol (pharmacology)
• Animals
• Apoptosis (drug effects)
• Caspase 3
• Caspase Inhibitors
• Caspases (metabolism)
• Endothelium (cytology)
• Enzyme Inhibitors (pharmacology)
• Glutathione (pharmacology)
• Insulin (pharmacology)
• Liver (cytology)
• Liver Transplantation
• Male
• Organ Preservation (methods)
• Organ Preservation Solutions
• Raffinose (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (drug therapy, pathology)