title: 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.affiliation: Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, MN 55905, USA.
authors.forename: Shiho
authors.initials: S
authors.lastname: Natori
authors.forename: Hajime
authors.initials: H
authors.lastname: Higuchi
authors.forename: Patricia
authors.initials: P
authors.lastname: Contreras
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004727:Endothelium / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000166:cytology*; D016031:Liver Transplantation; D008297:Male; D009926:Organ Preservation / Q000379:methods*; D019188:Organ Preservation Solutions; D011887:Raffinose / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000473:pathology
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007328:Insulin; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose