Harmful Waste Products as Novel Immune Modulators for Treating Inflammatory Arthritis 英文参考文献.docVIP

respPectives Harmful Waste Products as Novel Immune Modulators for Treating In?ammatory Arthritis? Andrew P. Cope The Role of Reactive Oxygen Species For many years, reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and hydroxyl radicals, and their reaction products, were classically described as harmful by-products of aerobic metabolism capable of causing DNA mutations, lipid peroxidation, and protein oxidation [1]. The identi?cation of enzymes such as superoxide dismutase, catalase, and peroxidase that served to eliminate these waste products rather substantiated this view. It soon became clear, however, that there existed a family of enzymes whose function it was to deliberately generate ROS. The ?rst of these was NADPH oxidase, which is responsible for the respiratory burst in neutrophils and macrophages in response to microbes or in?ammatory cytokines [2]. The DOI: 10.1371/journal.pmed.0030385.g001 catalytic centre of NADPH oxidase is the membrane-associated protein Figure 1. Structure and Function of the NADPH Oxidase Complex Schematic of the molecular composition of the NADPH oxidase complex. The principal subunits are shown, together with some of the key cellular and molecular modi?cations that arise following gp91 phox (see Glossary) complexed with . Activation requires association with a phosphorylated form of p47 (also known as Ncf1), p67 , and the small GTPase Rac (Figure 1). de?ciency in humans leads to p22 phox activation of stress pathways and the generation of superoxide (O ?). Two molecules of superoxide 2 phox can react to generate hydrogen peroxide (H O ). In the presence of iron, superoxide and H O 2 2 2 2 phox react to generate hydroxyl radicals (OH?). Through their effects on protein modi?cation and lipid peroxidation, reactive oxygen species exert pleiotropic effects on multiple molecular and cellular pathways. p47 phox neutrophil dysfunction and chronic granulomatous disease (CGD), a primary immunode?ciency di