This is the Scientific Surgery Archive, which contains all randomized clinical trials in surgery that have been identified by searching the top 50 English language medical journal issues since January 1998. Compiled by Jonothan J. Earnshaw, former Editor-in-Chief, BJS

RAGE blockade and hepatic microcirculation in experimental endotoxaemic liver failure. BJS 2013; 100: 1229-1239.

Published: 27th June 2013

Authors: A. Kuhla, J. Norden, K. Abshagen, M. D. Menger, B. Vollmar

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.

Method

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.

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.

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