RAGE blockade and hepatic microcirculation in experimental endotoxaemic liver failure

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 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. SURGICAL RELEVANCE: The innate immune response to endoxaemia is initiated by a group of pattern recognition receptors, including the receptor for advanced glycation endproducts (RAGE). As RAGE is well known for perpetuation of inflammatory processes, blockade of this receptor might be of particular value in reducing or even halting endoxaemia-related organ disorders. Using intravital fluorescence microscopy this study demonstrated in vivo that pretreatment, but also post-treatment, with a RAGE-blocking antibody attenuated hepatic microcirculatory deterioration and leucocyte recruitment, and thus diminished liver injury in a murine model of endotoxaemic organ failure. These data underline the important role of RAGE in the innate immune response and support the potential therapeutic value of blocking this pattern recognition receptor.