Pretreatment with Mangafodipir Improves Liver Graft Tolerance to Ischemia/Reperfusion Injury in Rat

Ismail Ben Mosbah,Philippe Compagnon,Catherine Ribault,Alexis Laurent,Yann Mouchel,Anne Corlu,Karim Boudjema,Julie Pajaud,Fabrice Morel,Catherine Lucas

doi:10.1371/journal.pone.0050235

Abstract

Ischemia/reperfusion injury occurring during liver transplantation is mainly due to the generation of reactive oxygen species (ROS) upon revascularization. Thus, delivery of antioxidant enzymes might reduce the deleterious effects of ROS and improve liver graft initial function. Mangafodipir trisodium (MnDPDP), a contrast agent currently used in magnetic resonance imaging of the liver, has been shown to be endowed with powerful antioxidant properties. We hypothesized that MnDPDP could have a protective effect against liver ischemia reperfusion injury when administrated to the donor prior to harvesting. Livers from Sprague Dawley rats pretreated or not with MnDPDP were harvested and subsequently preserved for 24 h in Celsior® solution at 4°C. Organs were then perfused ex vivo for 120 min at 37°C with Krebs Henseleit solution. In MnDPDP (5 µmol/kg) group, we observed that ATP content was significantly higher at the end of the cold preservation period relative to untreated group. After reperfusion, livers from MnDPDP-treated rats showed better tissue integrity, less hepatocellular and endothelial cell injury. This was accompanied by larger amounts of bile production and higher ATP recovery as compared to untreated livers. The protective effect of MnDPDP was associated with a significant decrease of lipid peroxidation, mitochondrial damage, and apoptosis. Interestingly, MnDPDP-pretreated livers exhibited activation of Nfr2 and HIF-1α pathways resulting in a higher catalase and HO-1 activities. MnDPDP also increased total nitric oxide (NO) production which derived from higher expression of constitutive NO synthase and lower expression of inducible NO synthase. In conclusion, our results show that donor pretreatment with MnDPDP protects the rat liver graft from cold ischemia/reperfusion injury and demonstrate for the first time the potential interest of this molecule in the field of organ preservation. Since MnDPDP is safely used in liver imaging, this preservation strategy holds great promise for translation to clinical liver transplantation.

Highlights

Liver transplantation has been established as the most effective and durable therapy for end-stage liver disease [1]
lactate dehydrogenase (LDH) and ALT levels in livers of rats pretreated with MnDPDP at a concentration of 3 mmol/kg and 15 mmol/kg were similar to those observed in I/ R group
In this study, using an isolated perfused rat liver model, we demonstrate for the first time that MnDPDP protects the rat liver from cold I/R injury when administrated to the donor prior to liver harvesting

Summary

Introduction

Liver transplantation has been established as the most effective and durable therapy for end-stage liver disease [1]. Ischemia and subsequent reperfusion are unavoidable causes of graft injury in the current practice of organ transplantation and represent a major risk factor for graft dysfunction [5,6]. This multifactorial and interdependent damage process has become even more significant with increasing use of marginal grafts to meet the current growing demands [7]. Donor pretreatment leads to the maintenance of liver energetic status, attenuation of oxidative stress, mitochondrial damage and apoptosis, as well as an enhancement of nitric oxide production This protective effect is associated with the activation of Nrf and HIF-1a pathways

Materials and Methods

Results

Discussion