Reactive Metabolites and AGE-RAGE-Mediated Inflammation in Patients following Liver Transplantation

Thorsten Brenner,Thomas Bruckner,Eike O Martin,Peter Schemmer,Stefan Hofer,Thomas H Fleming,Markus A Weigand,David Spranz,Florian Uhle

doi:10.1155/2013/501430

Abstract

Recent investigations have indicated that reactive metabolites and AGE-RAGE-mediated inflammation might play an important role in the pathogenesis of ischemia-reperfusion injury in liver transplantation. In this observational clinical study, 150 patients were enrolled following liver transplantation from deceased donors. The occurrence of short-term complications within 10 days of transplantation was documented. Blood samples were collected prior to transplantation, immediately after transplantation, and at consecutive time points, for a total of seven days after transplantation. Plasma levels of methylglyoxal were determined using HPLC, whereas plasma levels of L-arginine, asymmetric dimethylarginine, advanced glycation endproducts-carboxylmethyllysine, soluble receptor for advanced glycation endproducts, and total antioxidant capacity were measured by ELISA. Patients following liver transplantation were shown to suffer from increased RAGE-associated inflammation with an AGE load mainly dependent upon reactive carbonyl species-derived AGEs. In contrast, carboxylmethyllysine-derived AGEs were of a minor importance. As assessed by the ratio of L-arginine/asymmetric dimethylarginine, the bioavailability of nitric oxide was shown to be reduced in hepatic IRI, especially in those patients suffering from perfusion disorders following liver transplantation. For the early identification of patients at high risk of perfusion disorders, the implementation of asymmetric dimethylarginine measurements in routine diagnostics following liver transplantation from deceased donors should be taken into consideration.

Highlights

Liver transplantation (LTPL) is a routinely used therapeutic option in patients with end-stage liver disease
ischemia-reperfusion injury (IRI)-associated immunoinflammatory processes consist of two related stages: (i) immune-triggering stage: cellular stress or damage due to hepatic IRI leads to the generation of alarmins; these danger molecules are known to activate liver resident Kupffer cells (KC) as well as dendritic cells (DC) throughout the corresponding pattern recognition receptors (PRR: e.g., receptor for advanced glycation endproducts (RAGE)), subsequently boosting immunoinflammatory responses, and (ii) immune-sustaining stage: circulating mononuclear and polymorphonuclear cells become activated and recruited into sites of IRI in order to sustain local immune responses, resulting in an amplification of local tissue damage (Figure 1) [45]
In this setting cellular advanced glycation endproducts (AGEs) load was demonstrated to be mainly dependent on reactive carbonyl species (RCS)-derived AGEs, whereas CML-derived AGEs seem to be of minor importance

Summary

Introduction

Liver transplantation (LTPL) is a routinely used therapeutic option in patients with end-stage liver disease. Several investigations have suggested that reactive oxygen species (ROS: e.g., O2−) may be important mediators of reperfusion injury in IRI [7,8,9,10,11,12], leading to protein and deoxyribonucleic acid (DNA) oxidation, lipid peroxidation, and the interaction with other intracellular and extracellular radical species, such as reactive nitrogen species (RNS: e.g., nitric oxide/NO) [13,14,15]. This interaction is known to produce the potent cytotoxic oxidizing and nitrating species peroxynitrite (ONOO−) and its conjugate peroxynitrous acid (HONOO). NO has been demonstrated to be an important hepatoprotective molecule, as decreased NO bioavailability is associated with impaired microcirculatory blood flow and increased

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