Evaluation of IGL-1 preservation solution using an orthotopic liver transplantation model

AIM： To compare, in a pig the protective effect of UW liver transplantation model, with that of IGL-1, a highsodium preservation solution containing polyethylene glycol （PEG） as an oncotic supply. METHODS： All livers were harvested and grafted orthotopically according to standard techniques. The livers were washed out and preserved for 7 h in IGL-1 （n = 6） or in UW solution （n = 7） at 4℃. In a sham group （n = 4）, the livers underwent a 60-min warm ischemia at 37℃. The hepatocellular injury was assessed in organ preservation solution washed out from the graft at the end of ischemic storage （before revascularization）, and in serum 2 h after reperfusion and daily for up to 6 d. RESULTS： Livers preserved in IGL-1 solution released markedly less AST than that preserved in the UW solution before and after revascularization （P 〈 0.05）. Besides, the activity of creatine kinase-BB, a marker of sinusoidal lining cells injury, was higher in the UW group than in the IGL-1 group （P 〈 0.05）. Histological results showed less necrotic regions in livers preserved in IGL-1 solution; however, no difference was observed for inflammation. CONCLUSION： IGL-1 liquid effectively protects parenchymal and non-parenchymal cells against preservation-reperfusion injuries.

Hypoxia inducible factor-1αaccumulation in steatotic liver preservation:Role of nitric oxide

AIM:To examine the relevance of hypoxia inducible factor(HIF-1)and nitric oxide(NO)on the preservation of fatty liver against cold ischemia-reperfusion injury(IRI). METHODS:We used an isolated perfused rat liver model and we evaluated HIF-1αin steatotic and non-steatotic livers preserved for 24 h at 4℃in University of Wisconsin and IGL-1 solutions,and then subjected to 2 h of normothermic reperfusion.After normoxic reperfusion,liver enzymes,bile production,bromosulfophthalein clearance,as well as HIF-1αand NO[endothelial NO synthase(eNOS)activity and nitrites/nitrates]were also measured.Other factors associated with the higher susceptibility of steatotic livers to IRI,such as mitochondrial damage and vascular resistance were evaluated. RESULTS:A significant increase in HIF-1αwas found in steatotic and non-steatotic livers preserved in IGL-1 after cold storage.Livers preserved in IGL-1 showed a significant attenuation of liver injury and improvement in liver function parameters.These benefits were enhanced by the addition of trimetazidine(an antiischemic drug),which induces NO and eNOS activation, to IGL-1 solution.In normoxic reperfusion,the presence of NO favors HIF-1αaccumulation,promoting also the activation of other cytoprotective genes,such as hemeoxygenase-1. CONCLUSION:We found evidence for the role of the HIF-1α/NO system in fatty liver preservation,especially when IGL-1 solution is used.

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

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 nonfunction 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, anticytokines, 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.