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

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Abstract
AIM: To investigated 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 100 μmol/(h·kg), n = 5 each) was continuously administered via the jugular vein. RESULTS: Two hours after starting reperfusion plasma ALT increased to 1 457 ± 281 U/L (mean ± SE) in controls but to only 908 ± 187 U/L (P < 0.05) in animals treated with 100 μmol GSH/(h·kg). No protection was conveyed by 50 μmol GSH/(h·kg). Cytoprotection was confirmed by morphological findings on electron microscopy: GSH treatment prevented detachment of sinusoidal endothelial cells (SEC) 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 50 μmol and 100 μmol GSH/(h·kg), plasma GSH increased to 65 ± 7 mol/L and 97 ± 18 mol/L, but to only 20 ± 3 mol/L in untreated recipients. Furthermore, plasma glutathione disulfide (GSSG) increased to 7.5 ± 1.0 mol/L in animals treated with 100 μmol/(h·kg) GSH but did not raise levels of untreated controls (1.8 ± 0.5 mol/L) following infusion of 50 μmol GSH/(h·kg) (2.2 ± 0.2 mol/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.