Protective effect of the lazaroid U74006F in cold ischemia-reperfusion injury of the liver

Abstract

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)

Attenuation of Multiple Organ Dysfunction in a Chronic Sheep Model by the 21-Aminosteroid U74389G

“…A further increase of sorbitoldehydrogenase (up to Day 10 in control animals) was also diminished in the lazaroid group. These results are similar to data from Cosenza et al [21] who observed significantly lower ALT and AST release from livers pretreated with tirilazad 2 and 7 days after liver transplantation in pigs. Liu et al [24] also observed this effect in a model of liver ischemia/reperfusion and endotoxinemia in rats.…”

“…Lazaroids have demonstrated efficacy in animal models of acute central nervous system injuries sonable to suspect a similar mechanism is in effect in the present animal model. Although Fisher and co- [16], cerebral ischemia [17], hemorrhagic shock [7], traumatic shock [5], acute renal ischemia [18], splanchnic artery occlusion shock [19], cardiopulmonary arrest [20], liver ischemia [21], acute lung injury [22], endotoxinemia [23], and sepsis [6].…”

Ischemic cholangiopathy

“…Experimental studies in liver allograft indicate that preservation and reperfusion injury is mediated by thrombotic and ischemic events due to endothelial activation [30,[128][129][130][131][132]. In liver recipients, cholangiopathy occurs more frequently when ABO incompatible donors are used [14,119,120].…”

Changes in Hepatic Venous Oxygen Saturation in Hepatic Warm Ischemia/Reperfusion Injury in Pigs

“…Although I/R injury has been treated or prevented by some pharmaceuticals such as superoxide dismutase, 5 Lazaroid, 8 prostaglandin E 1 , 9 pentoxifylline, 10 and interleukin-1 receptor blockade, 11 their effects are usually evaluated by the outcome of the liver. However, the evaluation of ongoing I/R injury after reperfusion is necessary to determine whether these pharmaceuticals are effective or need additional complementary pharmaceutical treatment.…”