Melatonin protects steatotic and non steatotic liver grafts against cold ischemia and reperfusion injury

Chronic organ-donor shortage has required the acceptance of steatotic livers for transplantation purposes despite the higher risk of graft dysfunction or non-function associated with the cold ischemia-reperfusion injury. This study evaluated the use of melatonin as an additive to Institute Georges Lopez (IGL-1) solution for protecting nonsteatotic and steatotic liver grafts against cold ischemia-reperfusion injury.In the current investigation, we used an ex vivo isolated perfused rat liver model. Steatotic and nonsteatotic livers were preserved for 24 h (4ºC) in University of Wisconsin or IGL-1 solutions with or without melatonin, as well as in UW solution alone. Thereafter, livers were subjected to 2h- reperfusion (37ºC). We assessed hepatic injury (transaminases) and function [bile production and sulfobromophthalein (BSP) clearance, vascular resistance], as well as other factors potentially implicated in the high vulnerability of steatotic livers against ischemia–reperfusion injury (oxidative stress and related inflammatory mediators including nitric oxide and cytokines). We also evaluated well known cytoprotective factors as hemeoxygenase 1 (HO-1). Fatty livers preserved in IGL-1 solution enriched with melatonin showed lower transaminase levels and higher bile production and BSP clearance when compared to those obtained for livers maintained in IGL-1 solution alone. A significant diminution of vascular resistance was also observed when melatonin was added to the IGL-1 solution. The melatonin benefits correlated with the generation of nitric oxide (through constitutive e-NOS activation) and the prevention of oxidative stress and inflammatory cytokine release including tumour necrosis factor and adiponectin, respectively. The addition of melatonin to IGL- 1 solution improved non-steatotic and steatotic liver graft preservation, limiting their risk against cold ischemia-reperfusion injury.