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

Abstract

: Chronic organ‐donor shortage has required the acceptance of steatotic livers for transplantation purposes despite the higher risk of graft dysfunction or nonfunction 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 hr (4°C) in University of Wisconsin or IGL‐1 solutions with or without melatonin, as well as in University of Wisconsin solution alone. Thereafter, livers were subjected to 2‐hr reperfusion (37°C). 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 tumor necrosis factor and adiponectin, respectively. The addition of melatonin to IGL‐1 solution improved nonsteatotic and steatotic liver graft preservation, limiting their risk against cold ischemia–reperfusion injury.

Effect of Hepatic Steatosis on Bioenergetic Function During Hepatic Ischemia-reperfusion: A Systematic Review

“…Twenty-seven studies utilizing the thiobarbituric acid reactive substances assay showed significantly increased levels of MDA in steatotic livers post-IRI [20,21,23,25,28,32,34,38,40,44,46,48,52,54,55,57,[61][62][63]69,[71][72][73][75][76][77][78] while Nakano and colleagues [17] reported similar levels of perfusate MDA to that seen from lean livers. Serviddio et al [47] also reported a significant increase in mitochondrial 4-hydroxy-2-nonenal-protein adducts post-IRI in steatotic livers.…”

“…Eight of the 63 studies reported HO-1 levels in steatotic livers. Four studies reported a greater increase in HO-1 levels in steatotic livers post-warm IRI [20,21,31,35] whereas in cold PRI, 2 studies showed similar increase in HO-1 levels in both types of liver [69,74] and another two studies showed decreased HO-1 protein levels in steatotic livers [60,76].…”

“…Six studies measured levels of O 2 .-and steatotic livers were shown consistently to have increased levels of O 2 .-pre- [107] and post-IRI [23,63,66,69,75]. Interestingly, Nardo and colleagues [63] [32,47].…”

“…QUORUM Diagram. [18]; b, [19]; c, [20]; d, [21]; e, [22]; f, [23], g, [24]; h, [25]; i, [26]; j, [27]; k, [28]; l, [29]; m, [30]; n, [17]; o, [31]; p, [32]; q, [33]; r, [34]; s, [35]; t, [36]; u, [37] [38]; b, [39]; c, [40]; d, [41]; e, [42]; f, [43]; g, [44]; h, [45]; i, [46]; j, [47]; k, [48]; l, [49]; m, [50]; n, [51]; o, [52] [62]; c, [63]; d, [64]; e, [65]; f, [66]; g, [67]; h, [68]; i, [69]; j, [70]; k, [71]; l, [17]; m, [60]; n, [72]; o, [73]<...>…”

“…However, other enzymes such as xanthine oxidase (XOD), nicotinamide adenine dinucleotide phosphate-oxidase and monoamine oxidase [94,99] also [23,63,66,69,75,107]; c, [32,47]; d, [54,57]; e, [55,57]; f, [57]; g, [20,21,23 [87]. ONOO.-has been shown to irreversibly inhibit most components of the ETS including complex I-III [101] leading to impaired oxidative phosphorylation.…”