Investigations of the redox processes in inflammatory response and associated pathologies

Abstract

During the JP-1 project we demonstrated that the oxidation of uric acid by neutrophil-peroxidases and production of urate hydroperoxide is an important event during the inflammatory oxidative burst. Urate hydroperoxide preferentially oxidized peroxiredoxins and the extracellular cell surface protein disulfide isomerase (PDI) and might affect redox signaling, inflammation, atherosclerosis and vascular remodeling. The oxidation of uric acid was significantly correlated with carotid intima-media thickness (c-IMT) in patients with subclinical atherosclerosis and the product allantoin was purposed as an independent marker for atherosclerosis. The oxidation of uric acid by neutrophil-myeloperoxidase decreased the production of hypochlorous acid and the killing activity of these cells. The relevance of this study consists in the intense debate whether uric acid plays or not a causal role in cardiovascular disease. These debates are sustained by uncertainties on the exact mechanisms of how uric acid would cause/propagate tissue damage and, therefore, an appropriate intervention regarding uric acid levels in disease has been usually neglected. Our hypothesis is that the metabolic transformation of uric acid and production of reactive oxidant intermediates could sustain inflammation by affecting cell response and vascular homeostasis. Therefore, one of the purposes of this JP-2 project is to investigate other sources for urate oxidation and production of urate hydroperoxide in the vascular system. We will investigate how this oxidation would affect extracellular matrix formation and vascular remodeling. Because urate hydroperoxide efficiently oxidizes thiol-proteins, we will seek for the role of these proteins in vascular endothelial cell function, vascular remodeling and redox signaling related to macrophage polarization. The oxidation of uric acid decreased the killing activity of neutrophil-like cells against Pseudomonas aeruginosa. In this JP-2 project we will test the clinical relevance of this effect by investigating the correlation between uric acid, allantoin and sepsis progression in patients admitted in the intensive care unit of the Hospital das Clínicas from USP. In summary, this JP-2 project intends to strength the knowledge about redox processes in inflammatory response to better understand the mechanisms of inflammation progression/resolution. Since the production of urate hydroperoxide is relevant in the inflammatory oxidative burst, the project is focused into determine its effects in the progression of inflammation in vascular homeostasis and in infection states. We will also investigate myeloperoxidase inhibitor candidates and the redox signaling dependent on peroxiredoxins because these two events are tightly related to urate hydroperoxide formation and biological effects. (AU)