S47 RAGE-mediated cytokine release from leukocytes: implications for systemic inflammation

Introduction Systemic inflammatory response syndrome (SIRS) is the physiological and biochemical changes that result from an inflammation of the body, which commonly occurs in patients after cardiac surgery necessitating cardiopulmonary bypass (snCBP). To date, attempts at targeting inflammatory mediators associated with SIRS have been largely unsuccessful. One reason is there is a need to identify mediators involved in SIRS with a wider therapeutic window—one possibility is RAGE. RAGE is a transmembrane receptor, which acts as a pattern recognition receptor and induces inflammation. RAGE has multiple ligands, which include S100B and HMGB-1 proteins. RAGE ligands are raised in patients with SIRS but effects of RAGE ligands on cytokine release from whole blood, which could contribute to the onset of SIRS, is not well characterised. This study investigates the effects of S100B and HMGB-1 on cytokine release in whole blood (WB) pre and post-snCPB. Methods Nine patients undergoing snCPB at the Royal Brompton Hospital were enrolled into the study. Blood was collected from patients pre- and post-snCPB. WB was incubated with PBS, LPS, S100B, or HMGB1 were added for 4h. Supernatants were collected and later assayed for IL-8 by ELISA (R&D) and IL-1b, IL-6, IL-8, IL-10, TNFa, IL-12p70 and IFN-g, by electrochemiluminescence multiplex analysis. Results S100B and LPS caused significant release of IL-8 from WB acquired pre-op (p Conclusion This study shows that S100B, like LPS, has pro-inflammatory activity in WB. Both stimuli had a hypo-responsive response post-snCPB. Current literature already describes the LPS response, but the response by S100B has not previously been reported. Therefore S100B, but not HMGB-1, could be a potential pharmaceutical target in reducing inflammation in snCPB patients with SIRS.