Role of the Neutrophil NADPH Oxidase and S100A8/A9 in the Pathophysiology of Chronic Inflammation

摘要: Reactive oxygen species (ROS) are low-molecular-weight inorganic and highly reactive compounds that are produced during normal aerobic cell metabolism. At low level, ROS have a transient mode of action and important physiological roles in maintaining intracellular cell redox status, physical-chemical properties of membranes, protein kinase and transcriptional factor activities. They participate in the regulation of many aspects of fundamental cellular function, including growth-specific and migration-related signalling pathways, gene expression, GTPase-dependent cytoskeletal rearrangements, cell proliferation and apoptosis. Multiple endogenous macromolecules, participating in cellular signalling networks, bear redox-active moieties (eg, methionine, cysteine, guanine) at functional regions that render them sensitive to ROS. Consequently, ROS emerge, not only as second messengers, but also as diffusible modulators able to produce stable secondary signalling molecules.A major source of ROS are phagocytic cells such as polymorphonuclear neutrophils that are found activated and adherent to the endothelium or migrating through the extravascular tissue matrix. ROS produced by neutrophils are designed to kill the invading pathogens and have an important role in priming the immune system. The phagocyte NADPH oxidase, also referred as NOX2, is composed of several membane-bound and cytosolic subunits that assemble rapidly in the phagosomal or plasma membrane (Fig. 1). This allows the concentrated release of ROS at sites of inflammation where the pathogen is located (Ohno et al., 1982) and diffusion over short distances …