A caspase inhibitor, IDN-6556, ameliorates early hepatic injury in an ex vivo rat model of warm and cold ischemia
✍ Scribed by Niel C. Hoglen; Dean M. Anselmo; Masamichi Katori; Marian Kaldas; Xiu-Da Shen; Karen L. Valentino; Charles Lassman; Ronald W. Busuttil; Jerzy W. Kupiec-Weglinski; Douglas G. Farmer
- Book ID
- 102467084
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 222 KB
- Volume
- 13
- Category
- Article
- ISSN
- 1527-6465
- DOI
- 10.1002/lt.21016
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✦ Synopsis
This study examined the efficacy of the caspase inhibitor, IDN-6556, in a rat model of liver ischemia-reperfusion injury. Livers from male Sprague-Dawley rats were reperfused for 120 minutes after 24 hours of 4°C cold storage in University of Wisconsin solution. Portal blood flow measurements estimated sinusoidal resistance, and bile production, alanine aminotransferase activities, and Suzuki scores were evaluated as parameters of hepatocyte/liver injury. Treated livers were exposed to 25 or 50 M of IDN-6556 in University of Wisconsin storage solution and/or the perfusate. All treatment regimens with IDN-6556 significantly improved portal blood flow measured at 120 minutes, and significant improvements were seen as early as 30 minutes when inhibitor was also present in the perfusate (P Ͻ 0.01). All treatment groups with IDN-6556 significantly increased bile production by 3-4-fold compared with controls (P Ͻ 0.01), and reductions in alanine aminotransferase activities were seen within 90 minutes of reperfusion (P Ͻ 0.05). These data were confirmed by improved Suzuki scores (less sinusoidal congestion, necrosis, and vacuolization) in all treated groups. Livers from the IDN-6556 -treated groups had markedly reduced caspase activities and TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-positive cells, suggesting reductions in apoptosis. IDN-6556 present in cold storage media ameliorated liver injury due to cold ischemia and reperfusion injury and may be a rational therapeutic approach to reduce the risk of liver ischemia in the clinical setting.