Reactive oxygen species (ROS) are molecules derived from oxygen. They are generated by professional NADPH oxidases (NOX). The NOX family are proteins that transfer electrons across biological membranes. In general, the electron acceptor is oxygen and the product of the electron transfer reaction is superoxide. Seven NOXs protein has been described and all of them generate or ROS. Despite their similar structure and enzymatic function, NOX family enzymes differ in their mechanism of activation, their tissue, cellular and subcellular localizations and in consequence their physiological functions. Physiological and pathological roles of NOX enzymes are usually discovered in transgenic mouse models. The goal of this thesis was to determine two new roles of NOX1 in human diseases: Hypertension and respiratory distress syndrome. Secondly, we have evaluated the anti-inflammatory role of NOX2 using Nox2-deficient mice. NOX1 has been involved in angiotensin II-induced hypertension. In this study, it has been demonstrated that NOX1-generated ROS have also implicated in angiotensin II-induced aneurysms. They can regulate the metallo-protease activity and fibrosis. NOX1 is activated by angiotensin II receptor (AT1) engagement. We have demonstrated that NOX1 also regulates the AT1 expression to the plasma membrane. NOX1 seems to be a possible therapeutical target in hypertension and aneurysm formation. The respiratory distress syndrome especially in premature babies is characterized by immature lung development. During respiratory distress syndrome treatment with mechanical ventilation and high oxygen concentration, the lungs are exposed to increased oxidative stress leading to pulmonary injury. During this study, we have demonstrated that Nox1 but not Nox2 participates to hyperoxie-induced lung injury. In Nox1-deficient mice, decreased ROS generation reduce cell death in alveolar epithelial and endothelial cells. NOX1 seems also to be a possible therapeutical target in respiratory distress syndrome. Chronic granulomatous disease (CGD) is an immunodeficiency syndrome due to mutations in gene gp91phox coding for NOX2 protein. In consequence, CGD patients suffer from severe and recurrent infections. Indeed, they present hyperinflammatory response which plays a role in the morbidity of the disease. During this study, we have demonstrated that a possible stimulus of this CGD inflammatory complication is the beta-glucans, in Nox2-deficient mice. These glucose polymers induce inflammation that cannot be resolved in absence of NOX2. Also, CGD hyperinflammation is characterized by important TNFalpha production. But the blockage of TNFalpha has not dampened CGD hyperinflammation. In the other hand, the blockage of the principal beta-glucans receptor, dectin-1 pharmacologically or genetically, has reduced significantly CGD hyperinflammation. These data constitute new therapeutical target in CGD inflammatory syndrome.
