GSH Attenuates Organ Injury and Improves Function after Transplantation of Fatty Livers

Abstract

Ischemia-reperfusion injury (IRI) is increased after transplantation of steatotic livers. Since those livers are increasingly used for transplantation, protective strategies must be developed. Reactive oxygen species (ROS) play a key role in hepatic IRI. In lean organs, glutathione (GSH) is an efficient scavenger of ROS, diminishing IRI. The aim of this study was to evaluate whether GSH also protects steatotic allografts from IRI following transplantation. Fatty or lean livers were explanted from 10-week-old obese or lean Zucker rats and preserved (obese 4 h, lean 24 h) in hypothermic University of Wisconsin solution. Arterialized liver transplantation was then performed in lean syngeneic Zucker rats. Recipients of fatty livers were treated with GSH (200 µmol/h/kg) or saline during reperfusion (2 h, n = 5). Parameters of hepatocellular damage and bile flow were measured. Transplantation of steatotic livers enhanced early reperfusion injury compared to lean organs as measured by increased aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase plasma levels. Bile flow was also reduced in steatotic grafts. Intravenous administration of GSH effectively decreased liver damage in fatty allografts and resulted in improved bile flow. Intravenous application of GSH effectively reduces early IRI in steatotic allografts and improves recovery of these marginal donor organs following transplantation.

Oxidative stress and apoptosis in a pig model of brain death (BD) and living donation (LD)

“…Among others, GSS is well known to detoxify hydrogen peroxide as well as peroxynitrate by increasing intracellular glutathione levels [38,39]. Recent studies examined the therapeutic potential of GSS, a compound of particular clinical interest in humans which is able to react spontaneously with nearly every oxidants formed during inflammation and reperfusion [40]. One of the first antioxidants investigated was the use of exogenous catalases as well as SOD [41].…”

Protocol TOP-Study (tacrolimus organ perfusion): a prospective randomized multicenter trial to reduce ischemia reperfusion injury in transplantation of marginal liver grafts with an ex vivotacrolimus perfusion

“…Marginal organs are increasingly accepted, which is associated with increased acute IRI [4,23] and diminished graft survival [5,25,26]. An increased susceptibility of marginal organs to the pathomechanisms of IRI is discussed as a potential cause for the impaired outcome of these grafts [2,3].…”

“…Based on a previous study using non-marginal healthy grafts, an effect size of approximately 0.5 was calculated [22]. In experimental studies, therapies for the treatment of IRI were more effective in steatotic livers [23,24]. Since recipients of marginal organs are incorporated in the present study, the predicted improvement in postoperative ALT levels should be higher than in non-marginal grafts.…”

Tacrolimus Preconditioning of Rat Liver Allografts Impacts Glutathione Homeostasis and Early Reperfusion Injury

“…During reperfusion of warm and cold ischemic livers, activated Kupffer cells (KC) produce mediators of inflammation, including tumor necrosis factor a, interleukins, and chemokines, and release ROS into the sinusoidal space, which in turn result in liver damage [26]. There is no doubt that I/R-mediated intracellular oxygen radical formation may contribute to hepatic failure [6,23,27]. In addition, we were recently able to demonstrate that the generation of KC-derived ROS may act as extracellular signal molecules, rendering also the sinusoidal space to an ''oxidative'' environment [3,8,20].…”

“…A large number of investigations using antioxidant interventions support the pivotal role of ROS in the development of reperfusion injury following warm or cold liver ischemia [3,6,7]. Recent studies examined the therapeutic potential of the endogenous antioxidant glutathione (GSH), a compound which is of particular clinical interest due to its low toxicity in humans [8].…”