Protective effect of the lazaroid U74006F in cold ischemia-reperfusion injury of the liver.
Lipid peroxidation may play a major role in the loss of liver graft viability after prolonged cold ischemia and reperfusion injury. The lazaroid compound U74006F is a potent inhibitor of lipid peroxidation, and this study was designed to evaluate the efficacy of this compound in preventing cold ischemia-reperfusion damage in three different models: pig endothelial cells in culture, ex vivo isolated pig liver perfusion and orthotopic transplantation of syngeneic rat livers. The addition of U74006F to University of Wisconsin preservation solution significantly prolonged endothelial cell viability after 48 and 72 hr of cold ischemia and reoxygenation (p < 0.01). Donor pigs were injected with vehicle or U74006F (4.5 mg/kg) before liver harvest. After 24 hr of cold storage in University of Wisconsin solution, the livers were perfused with pig blood for 180 min in an isolation chamber. Measurements of liver function parameters, including AST, ALT, bile production, superoxide anion and phospholipase A2 release, were assessed every 60 min. Although bile production was similar in the U74006F-treated and control groups, significant decreases of AST and ALT levels (p < 0.01) in the perfusate of the livers from treated donors were observed. In addition, the U74006F group displayed significantly reduced release of superoxide anion and phospholipase A2 compared with these parameters in the untreated group (p < 0.05 and p < 0.01, respectively). In the last model, donor rats were treated with U74006F before harvest; the rat liver grafts were preserved in cold University of Wisconsin solution for 24 hr and then transplanted into recipient rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Cosenza
C A
CA
Department of Surgery, Cedars-Sinai Medical Center, Beverly Hills, California 90211.
Cramer
D V
DV
Cunneen
S A
SA
Tuso
P J
PJ
Wang
H K
HK
Makowka
L
L
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003080:Cold Temperature / Q000009:adverse effects*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers; D006085:Graft Survival / Q000187:drug effects; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors*; D008099:Liver / Q000098:blood supply / Q000187:drug effects*; D016031:Liver Transplantation; D008297:Male; D009924:Organ Culture Techniques; D009926:Organ Preservation; D011281:Pregnatrienes / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D013552:Swine; D013556:Swine, Miniature
D016166:Free Radical Scavengers; D008054:Lipid Peroxides; D011281:Pregnatrienes; C053355:tirilazad