Glutathione protects the rat liver against reperfusion injury after hypothermic preservation

Background & Aims: The extracellular generation of reactive oxygen species (ROS) by Kupffer cells contributes to reperfusion injury of the liver allog raft. The endogenous antioxidant glutathione (GSH) can detoxify these ROS; however, this effect might be limited by the low extracellular concentratio n of GSH. We therefore investigated whether an increase of extracellular GS H protects the liver against reperfusion injury after Gold preservation. Me thods: Livers of male Sprague-Dawley rats subjected to 24 hours of cold isc hemia in University of Wisconsin solution (4 degrees C) were reperfused for 2 hours in the absence (controls) or presence of 0.5, 1, 2, or 4 mmol/L GS H (n = 4-6 each). Results: Two hours after starting reperfusion of control livers, the sinusoidal release of lactate dehydrogenase and purine nucleosi de phosphorylase increased to 247 +/- 96 and 27 +/- 13 mU . min(-1) . g liv er(-1), respectively, but only to 76 +/- 43 and 10 +/- 4 mU . min(-1) . g l iver-l in the presence of 4 mmol/L GSH. This cytoprotective effect was conf irmed histologically by a marked reduction of trypan blue staining of hepat ocytes. Compared with control livers, postischemic bile now was significant ly enhanced by GSH (0.15 +/- 0.02 vs. 0.41 +/- 0.11 mu L . min(-1) . g live r(-1)), indicating improved liver Function. During reperfusion of control l ivers, intracellular GSH content declined from 4.5 +/- 0.3 to 2.3 +/- 0.1 m u mol/g liver, but only to 3.8 +/- 0.4 mu mol/g liver in the presence of 4 mmol/L GSH. Reperfusion of untreated livers was accompanied by a prolonged increase of portal pressure to maximally 12.5 +/- 1.9 cm H2O, which was sig nificantly attenuated by 4 mmol/L GSH (7.2 +/- 1.4 cm H2O). Similar cytopro tective and hemodynamic effects were observed with 2 mmol/L GSH, but not wi th 0.5 and 1 mmol/L GSH. Conclusions: Treatment of cold-preserved livers wi th GSH upon reperfusion prevents damage of:hepatocytes, deterioration of th e hepatic circulation, and loss of intracellular GSM. In view of these prot ective effects and its low toxicity in humans, GSH should be considered a c andidate drug for prevention of ROS-related reperfusion injury of the liver allograft.