Polyethylene glycols: An effective strategy for limiting liver ischemia reperfusion injury

Abstract

Liver ischemia-reperfusion injury (IRI) is an inherent feature of liver surgery and liver transplantation in which damage to a hypoxic organ (ischemia) is exacerbated following the return of oxygen delivery (reperfusion). IRI is a major cause of primary non-function after transplantation and may lead to graft rejection, regardless of immunological considerations. The immediate response involves the disruption of cellular mitochondrial oxidative phosphorylation and the accumulation of metabolic intermediates during the ischemic period, and oxidative stress during blood flow restoration. Moreover, a complex cascade of inflammatory mediators is generated during reperfusion, contributing to the extension of the damage and finally to organ failure. A variety of pharmacological interventions (antioxidants, anti-cytokines, etc.) have been proposed to alleviate graft injury but their usefulness is limited by the local and specific action of the drugs and by their potential undesirable toxic effects. Polyethylene glycols (PEGs), which are non-toxic water-soluble compounds approved by the FDA, have been widely used as a vehicle or a base in food, cosmetics and pharmaceuticals, and also as adjuvants for ameliorating drug pharmacokinetics. Some PEGs are also currently used as additives in organ preservation solutions prior to transplantation in order to limit the damage associated with cold ischemia reperfusion. More recently, the administration of PEGs of different molecular weights by intravenous injection has emerged as a new therapeutic tool to protect liver grafts from IRI. In this review, we summarize the current knowledge concerning the use of PEGs as a useful target for limiting liver IRI.

Keywords: Ischemia reperfusion injury, Polyethylene glycol, Liver preconditioning, Liver transplantation, UW solution, IGL-1 solution, SCOT solution, PEG rinse solution, Machine perfusion

Core tip: Pharmacological treatments for preventing liver ischemia reperfusion injury are limited, due to the complex pathophysiology of this condition. The drugs currently used for preventing ischemia-reperfusion injury (IRI) all have local and specific activity with potentially damaging side effects. This review focuses on the current understanding of polyethylene glycols, which are non-toxic polymers, as new emerging agents for limiting liver IRI, and proposes directions for future investigations.