TY - JOUR
T1 - The caspase inhibitor IDN-6556 prevents caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury
AU - Natori, Shiho
AU - Higuchi, Hajime
AU - Contreras, Patricia
AU - Gores, Gregory J.
N1 - Funding Information:
From the *Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, MN; and †IDUN Pharmaceuticals, La Jolla, CA. Supported in part by grant no. DK41876 from The National Institutes of Health; and the Mayo Foundation. Address reprint requests to Gregory J. Gores, MD, Professor of Medicine, Mayo Medical School, Clinic, and Foundation, 200 First St SW, Rochester, MN 55905. Telephone: 507-284-0686; FAX: 507-284-0762; E-mail: gores.gregory@mayo.edu Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0903-0010$30.00/0 doi:10.1053/jlts.2003.50019
PY - 2003/3/1
Y1 - 2003/3/1
N2 - 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 transferase-mediated 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.
AB - 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 transferase-mediated 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.
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U2 - 10.1053/jlts.2003.50019
DO - 10.1053/jlts.2003.50019
M3 - Article
C2 - 12619025
AN - SCOPUS:0037342981
SN - 1527-6465
VL - 9
SP - 278
EP - 284
JO - Liver Transplantation
JF - Liver Transplantation
IS - 3
ER -