Intravenous administration of glutathione protects parenchymal and non-parenchymal liver cells against reperfusion injury following rat liver transplantation

摘要

AIM:To investigate the effects of intravenous administration of the antioxidant glutathione (GSH) on reperfusion injury following liver transplantation.METHODS:Livers of male Lewis rats were transplanted after 24 h of hypothermic preservation in University of Wisconsin solution in a syngeneic setting. During a 2-h reperfusion period either saline (controls,n=8) or GSH (50 or 100μmol/(h·kg),n=5 each) was continuously administered via the jugular vein.RESULTS:Two hours after starting reperfusion plasma ALT increased to 1 457±281U/L (mean±SE) in controls but to only 908_+187 U/L (P<0.05) in animals treated with 100μmol GSH/(h·kg).No protection was conveyed by 50μmol GSH/(h·kg).Cytoprotection was confirmed by morphological findings on electron microscopy:GSH treatment prevented detachment of sinusoidal endothelial cells (SECs) as well as loss of microvilli and mitochondrial swelling of hepatocytes. Accordingly, postischemic bile flow increased 2-fold. Intravital fluorescence microscopy revealed a nearly complete restoration of sinusoidal blood flow and a significant reduction of leukocyte adherence to sinusoids and postsinusoidal venules. Following infusion of 50μmol and 100 μmol GSH/(h·kg),plasma GSH increased to 65±7mol/L and 97±18μmol/L,but to only 20±3mol/L in untreated recipients.Furthermore, plasma glutathione disulfide (GSSG) increased to 7.5±1.0mol/L in animals treated with 100μmol/(h·kg) GSH but infusion of 50μmol GSH/(h·kg) did not raise levels of untreated controls (1.8±0.5mol/L vs 2.2±0.2mol/L).CONCLUSION:Plasma GSH levels above a critical level may act as a “sink” for ROS produced in the hepatic vasculature during reperfusion of liver grafts.Therefore, GSH can be considered a candidate antioxidant for the prevention of reperfusion injury after liver transplantation, in particular since it has a low toxicity in humans.