The Receptor for Advanced Glycation End-Products (RAGE) and its Ligands in Systemic Inflammation following Surgery Necessitating Cardiopulmonary Bypass

Abstract

Surgery necessitating cardiopulmonary bypass (snCPB) is associated with systemic inflammation which can be severe. Systemic inflammation is common in the critically ill, is associated with adverse outcome and currently has no specific therapy. Insight into the pathogenesis of systemic inflammation may lead to therapies. The receptor for advanced glycation end-products (RAGE) may represent a novel target for intervention. RAGE is a ubiquitous multi-ligand receptor that is up-regulated in the presence of its ligands. Initially characterised as a receptor for glycated proteins, it is also binds the S100 proteins and high mobility group box 1 (HMGB1); causing pro-inflammatory responses via NF-κB and the MAP kinases. RAGE inhibition has been associated with improved outcomes in animal models of infectious and sterile systemic inflammation. Of the snCPB patients assessed (n=2440) for relationships between age (associated with RAGE up-regulation) with systemic inflammation and clinical outcome, the oldest patients met more SIRS criteria in the first 1h and 24h following snCPB than those aged 40-80 y. This was accompanied by higher scores of organ dysfunction. Also, plasma levels of RAGE ligands and soluble RAGE increased (n=18-120) around surgery with pre-operative levels correlating with duration of intensive care. Leukocyte cell-surface and intracellular levels of RAGE were assessed and cell surface levels on neutrophils decreased following surgery, possibly contributing to the sRAGE levels in plasma. Cytokine release from whole blood increased following incubation with RAGE ligands, with a diminished effect on whole blood obtained after snCPB, suggesting leukocyte hypo-responsiveness. Finally, genotyping 8 single nucleotide polymorphisms in the RAGE, HMGB1 and S100A8 genes in 187 snCBP patients indicated statistically significant relationships to clinical outcomes such as impaired oxygenation and incidence of acute kidney injury. The findings from these investigations, inform understanding of the involvement of the RAGE axis in systemic inflammation.