Protection by cyclosporine A against normothermic liver ischemia-reperfusion in pigs.

BACKGROUND: Cyclosporine A (CYA) is primarily utilized as an immunosuppressant, but its mechanisms of action (including decreased neutrophilic free radical production and stabilization of mitochondrial and lysosomal membranes) may have beneficial effects in ischemia and reperfusion (IR) injury. This study was undertaken to examine the effect of CYA pretreatment on porcine liver histopathologic changes and enzymatic release caused by ischemia and reperfusion. MATERIALS AND METHODS: CYA was administered orally for 4 days prior to surgery in two doses (10 or 20 mg/kg) while controls received only the control vehicle. Pigs were then exposed to 4 h of hepatic ischemia followed by 2 h of reperfusion. RESULTS: Significant decreases in AST levels compared to controls were seen in high dose CYA pigs at the end of ischemia and at 30-min intervals during the reperfusion period. Controls exhibited necrotic hepatocytes and severe inflammatory cell infiltration, while high dose CYA animals demonstrated mild inflammatory cell infiltrates. Controls had decreased survival--20% did not survive reperfusion. CONCLUSIONS: This study indicates that CYA may be useful in decreasing initial damage resulting from warm hepatic IR injury.

Effect of pentoxifylline on hepatic ischemia and reperfusion injury.

BACKGROUND: Although pentoxifylline has been shown to improve tissue oxygenation and restore hepatocellular function after hemorrhagic shock, its effect on hepatic ischemia and reperfusion injury has not been fully clarified. The purpose of this study was to determine whether pentoxifylline exerted beneficial effects on liver histopathologic changes and enzymatic release caused by ischemia and reperfusion. METHODS: Warm, reversible hepatic ischemia/reperfusion injury was induced in four groups of pigs. Preoperative oral (24 mg/kg or 50 mg/kg) or intraoperative intravenous (50 mg/kg) pentoxifylline was administered. Control animals received intravenous normal saline solution. RESULTS: Untreated control animals exhibited significant liver damage expressed by hepatic histopathologic changes and high plasma levels of aminotransferases. Decreased animal survival was seen in the untreated group. All treated animals survived. Pentoxifylline given orally did not improve histopathologic changes or enzyme release. Intravenous administration caused significant amelioration of liver tissue damage, marked reduction of aspartate aminotransferase levels, and mild attenuation of alanine aminotransferase levels, as compared with control. CONCLUSIONS: This study indicates that intraoperative, intravenous pentoxifylline reduces hepatic injury after warm ischemia and reperfusion.

Development of an in situ isolated porcine liver perfusion model for tightly controlled physiologic and pharmacologic studies.

Several types of isolated perfused porcine liver models have been proposed for the study of hepatic assist, preservation injury, and specific physiologic or pharmacologic mechanisms. The development of a more general in situ isolated perfused model applicable to a broad range of studies is presented. This model eliminates or minimizes the shortcomings of previous models including ischemic injury prior to perfusion, limited range of vascular pressures and flows, nonphysiologic sources of portal and hepatic artery perfusion, and coupling of the liver to uncontrolled whole-body homeostatic mechanisms. Essentially the model as presented can be described as an autologous transplanted liver without preservation or ischemic injury, functioning within an adrenalectomized, cardiac output and temperature-controlled animal. Independent control of the dual hepatic vascular supply is maintained with pulsatile perfusion of the hepatic artery from the left atrium and nonpulsatile perfusion of the portal vein via the portal system. Oxygenators are not required. Hepatic vein pressure can be controlled independently of hepatic blood flow and systemic hemodynamics. Pharmacologic studies are not restricted to drugs whose termination of action is limited to hepatic metabolism because normal routes of drug redistribution, metabolism, and excretion are present. The model exhibits normal oxygen metabolism and classic control of hepatic artery resistance by portal vein blood flow. There are rather obvious significant advantages inherent in this model for tightly controlled hepatic physiologic and pharmacologic studies.