Is melatonin suitable for increasing steatotic graft liver preservation?

Background and aims: Chronic organ-donor shortage led to the acceptance of steatotic livers for transplantation despite the risk of graft dysfunction or non-function associated with ischemic preservation and reperfusion. Institute Georges Lopez (IGL-1) solution has been successfully used to preserve steatotic livers. Melatonin (MEL) demonstrated to protect normal liver by improving mitochondria function and microcirculation, decreasing oxidative stress and inflammation. In this communication, we evaluate the effects of melatonin on fatty liver preservation. These benefits were compared with those obtained for TMZ when both additives were used for the IGL-1 supplementation. Methods: Steatotic livers from Zucker rats were preserved for 24h in IGL-1 with MEL (100μM), TMZ (10μM) and MEL+TMZ, and then perfused ex vivo for 2h at 37°C. Hepatic injury (AST/ALT) and function (bile production, vascular resistance and hepatic clearance of sulfobromophthalein), nitric oxide production (nitrite/nitrates & eNOS expression), oxidative stress (MDA) and inflammatory cytokines (TNF-alpha, IL-beta, adiponectin) production (Western blotting) were evaluated. Results: Steatotic livers preserved at 4ºC in IGL-1 solution enriched with MEL (IGL- 1+MEL), TMZ (IGL-1+TMZ) and MEL+TMZ (IGL-1+MEL+TMZ) showed lower ALT and AST release, increased bile production and increased hepatic clearance than livers preserved with IGL-1. This was substantiated by a significant diminution of vascular resistance when compared to the other groups, likely induced by increased nitric oxide generation by eNOS. Moreover, the combined action of MEL and TMZ contributed to prevent oxidative stress and cytokine release. Conclusions: The addition of MEL and TMZ to IGL-1 solution provided a better protection of steatotic livers against the deleterious effects of cold ischemia-reperfusion injury than IGL-1 solution alone. The exacerbated effect of MEL and TMZ thus appears as a very promising pharmacological approach for cold-storage preservation of marginal organs. MEL plays a specific action on fat cytokines, such as adiponectin after 2 hours of normothermic reperfusion.