Circulating levels of soluble receptor for advanced glycation end products and ligands of the receptor for advanced glycation end products in patients with acute liver failure

Abstract

Animal studies suggest that receptor for advanced glycation end products (RAGE)-dependent mechanisms contribute to acetaminophen-induced liver damage. We examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) or RAGE ligands, including extracellular newly identified receptor for advanced glycation end products binding protein (EN-RAGE), high-mobility group box 1 (HMGB1), and Nε-(Carboxymethyl)lysine adducts (CML), could aid in prognostication after an acetaminophen overdose. Sixty well-characterized acetaminophen-related acute liver failure (ALF) patients (30 spontaneous survivors and 30 patients who underwent transplantation and/or died) who were enrolled in the National Institutes of Health-sponsored Acute Liver Failure Study Group, were matched by age, met standard criteria for encephalopathy, and had an international normalized ratio > 1.5 were retrospectively studied. HMGB1, EN-RAGE, CML, and sRAGE were detected by enzyme-linked immunosorbent assay methods in sera from ALF patients and 30 healthy controls. Levels of sRAGE, EN-RAGE, and HMGB1 (but not CML) were significantly greater (P < 0.001) in ALF patients versus normal controls. The levels of sRAGE, HMGB1, and EN-RAGE were significantly higher (P = 0.03, P < 0.01, and P = 0.03) in patients with a systemic inflammatory response syndrome (SIRS) score > 2 versus patients with a SIRS score ≤ 2. Nevertheless, only sRAGE levels were significantly higher in patients who underwent transplantation and/or died versus spontaneous survivors (P < 0.001), and they were positively associated with conventional markers of liver disease severity. Multivariate logistic regression identified an encephalopathy grade > 2 as an independent predictor of an adverse outcome on admission (odds ratio, 13; 95% confidence interval, 2.3-73; P < 0.001). The RAGE-ligand axis may interfere with liver regeneration and should be a promising objective for further research.

Figure 1. Serum levels of sRAGE, HMGB1 and EN-RAGE in relationship with the SIRS severity

Data are given as mean ± SEM. P-values by unpaired t-test, performed on the log-transformed data.

Figure 2. Schematic diagram of the RAGE-ligands release, inflammatory responses and feedback mechanism in RAGE ligands/RAGE/sRAGE system after injury induced by acetaminophen overdose

(1) Highly toxic metabolites produced by acetaminophen induce initial cell death resulting in diverse “danger” molecules including HMGB1, which, probably in conjunction with other inflammatory mediators, activate RAGE signaling on hepatic cells and/or dendritic cells and inflammatory cells. Ligand – RAGE interaction can lead to the activation of the MAPK pathways and the translocation of the transcription factor NF-κB from the cytosol to the nucleus, resulting in the up-regulation of genes involved in cellular inflammatory responses. (2) Then, these mediators, in an autocrine or paracrine manner, lead to receptor‐triggered transcriptional pathways resulting in the production of further pro-inflammatory mediator substances to create full‐scale tissue inflammation. (3) Although the exact mechanisms are still unclear, plausibly high levels of sRAGE are part of a counter – regulatory mechanism elicited by inflammation/injury and other pathological situations, such as renal failure that enhancing the expression of RAGE and its ligands, result in increased accumulation of sRAGE as a negative feedback on RAGE interactions with its ligands (4).