Immune complex-induced, nitric oxide-mediated vascular endothelial cell death by phagocytes (BA7P.159)

Abstract

Abstract Immune-complex (IC) mediated vascular endothelial cell death linked to the release of toxic free radicals by activated inflammatory cells. In particular, nitric oxide (NO), a highly reactive free radical, is implicated in many IC-mediated inflammatory disorders. However, the mechanisms of NO-induced endothelial cells death during autoimmune vasculitis have not been clearly understood. Therefore, we investigated the molecular mechanisms of extracellularly secreted NO by IC-activated phagocytes on endothelial cells using in-vitro and in-vivo vasculitis models. When co-incubation of antibody-coated endothelial cells, murine macrophages released significantly high levels of NO (12 folds) into the culture media. In addition exogenously added NO induced upregulation of pro-apoptotic genes such as Bax (15 fold), Bak (35 fold), cytochrome-C (11 fold) and caspase-3 (30 fold) in endothelial cells. Further, in vivo studies revealed that circulating ICs deposit and lead to accumulation of inflammatory cells in the capillaries but not in large arteries. In addition, the IC-mediated damages to vascular endothelium are prevented by uncoupling IC and inflammatory cells interaction. In summary these results suggest that, though the complexity of NO-induced cell death signaling exists due to its differential (dichotomous) cellular activities, it is absolutely dangerous for cell survival at sustained and chronic level of production as possibly occurring in IC-mediated autoimmune vasculitis