RAGE blockade and hepatic microcirculation in experimental endotoxaemic liver failure

Abstract

Abstract Background Activation of the receptor for advanced glycation endproducts (RAGE) causes sustained activation of multiple inflammatory pathways. Therefore, RAGE has potential as a new therapeutic target in sepsis. The aim of this study was to analyse whether RAGE blockade in vivo prevents microcirculatory dysfunction and subsequent tissue injury in endotoxaemic liver failure. Methods The hepatic microcirculation was analysed using intravital fluorescence microscopy in murine livers exposed to galactosamine/lipopolysaccharide (G/L) and treated with an anti-RAGE antibody (abRAGE) either 12 h before or 1 h after exposure to G/L. Blood and liver tissue samples were harvested for analysis of leucocyte tissue infiltration, apoptotic and necrotic damage as well as RAGE downstream pathway signalling. Results Sinusoidal perfusion failure in livers exposed to G/L was reduced significantly by both pretreatment and post-treatment with abRAGE. Hepatic inflammation induced by exposure to G/L was also attenuated by abRAGE administration, as shown by a 55 per cent reduction in sinusoidal leucocyte stasis, a 65 per cent decrease in venular leucocyte rolling and adhesion, and an 85 per cent reduction in leucocyte tissue infiltration. Treatment with abRAGE markedly reduced hepatocellular apoptosis and necrosis in livers exposed to G/L, and blunted the rise in plasma high-mobility group protein B1 levels. Finally, G/L-induced activation of the mitogen-activated protein kinase cascade was also reduced significantly by blockade of RAGE. Conclusion RAGE plays an important role in mediating endotoxaemic liver damage. RAGE blockade may have potential therapeutic value.