Neutrophils and other circulating phagocytes generate high levels of reactive oxygen species (ROS) in response to a variety of infectious or inflammatory stimuli in a process known as the respiratory burst. This response is attributed to the activity of NADPH oxidase, which produces superoxide, a precursor of ROS that are important microbicidal agents and mediators of inflammation. Patients with chronic granulomatous disease (CGD) have NADPH oxidase deficiencies and suffer from enhanced susceptibility to microbial infections and aberrant inflammatory responses. This project explores the cellular mechanisms regulating the respiratory burst in phagocytes and is characterizing oxidative responses of related enzymes expressed in a variety of non-immune cells. In work aimed at defining signal transduction pathways triggering activation of the phagocyte oxidase (phox), we have engaged gene transfection approaches to demonstrate involvement of the small GTPase, ADP-ribosylation factor-6 (ARF-6), and phospholipase D in the respiratory burst. Information on signaling intermediates affecting the respiratory burst in phagocytes will provide a basis for therapeutic strategies (pharmacological targets) designed to inhibit or enhance oxidative responses of phagocytes. In other studies we are characterizing sources of reactive oxygen species in other tissues (brain, vascular tissue, colon, kidney, thyroid and salivary glands). In these sites, the oxidants may serve in host defense or inflammatory reactions or provide redox """"""""second messengers"""""""" that affect gene expression patterns (proliferation responses to growth factors, differentiation, cellular senescence, apoptosis or programmed cell death, oxygen sensing). Studies in the p47phox-deficient mouse model of CGD indicate an essential role for p47phox in the release of reactive oxidants by microgial cells in response to neutrophil agonists or amyloid-beta, which may relate to neurodegenerative processes associated with Alzheimer's disease. The normal oxidative responses of aortic smooth muscle cells to PDGF or angiotensin II are also absent in p47phox-deficient mice, indicating involvement of a phagocyte-like oxidase in vascular tissue. Finally, transgenic mouse models (gene """"""""knock-out"""""""" and conditional antisense """"""""knock-down"""""""") in which oxidase components (Nox 4, Nox 1 and p22phox) are altered are currently under development to explore the roles of these systems in health and disease.
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