Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species

Abstract

Ischemia-reperfusion is a major component of injury in vascular occlusion both during liver surgery and during liver transplantation. The pathophysiology of hepatic ischemia-reperfusion includes a number of mechanisms including oxidant stress that contribute to various degrees to the overall organ damage. A large volume of recent research has focused on the use of antioxidants to ameliorate this injury, although results in experimental models have not translated well to the clinic. This review focuses on critical sources and mediators of oxidative stress during hepatic ischemia-reperfusion, the status of current antioxidant interventions, and emerging mechanisms of protection by preconditioning. While recent advances in regulation of antioxidant systems by Nrf2 provide interesting new potential therapeutic targets, an increased focus must be placed on more in-depth mechanistic investigations in hepatic ischemia-reperfusion injury and translational research in order to refine current strategies in disease management.

Fig. 1

Plasma alanine aminotransferase (ALT) activities (A) and hepatic content of 9-hydroxy eicosatetraenoic acid (HETE) (B) were measured in control livers, after 45-min ischemia to the median and left lobes plus 1-h reperfusion, and after 45-or 90-min continuous infusion of 0.8 μmol tert-butylhydroperoxide/min/g liver into the portal vein. All values represent means±SE of n=4. *p<0.05 (compared to controls). Data adapted from Mathews et al. [53].

Fig. 2

Mechanisms of ischemic and inflammatory injury and some potential antioxidant intervention strategies for hepatic ischemia reperfusion injury. Abbreviations: c5a, complement factor 5a; CXC, chemokines; HMGB1, high-mobility group box 1 protein; IL-1, interleukin 1; TNF-α, tumor necrosis factor-α; HO-1, heme oxygenase-1; MAPK, mitogen-activated protein kinase; A2AR, adenosine receptor 2a; HSPs, heat shock proteins; MnSOD, manganese superoxide dismutase; Nrf2, nuclear factor-erythroid 2 p45-related factor 2; GSH, glutathione; GSSG, glutathione disulfide; ROS, reactive oxygen species; H₂O₂, hydrogen peroxide; ONOO⁻, peroxynitrite; HOCl, hypochlorous acid; CT adducts, chlorotyrosine protein adducts; NT adducts, nitrotyrosine protein adducts.