Reactive Oxygen Species in Inflammation and Tissue Injury

Abstract

Reactive oxygen species (ROS) are key signaling molecules that play an important role in the progression of inflammatory disorders. An enhanced ROS generation by polymorphonuclear neutrophils (PMNs) at the site of inflammation causes endothelial dysfunction and tissue injury. The vascular endothelium plays an important role in passage of macromolecules and inflammatory cells from the blood to tissue. Under the inflammatory conditions, oxidative stress produced by PMNs leads to the opening of inter-endothelial junctions and promotes the migration of inflammatory cells across the endothelial barrier. The migrated inflammatory cells not only help in the clearance of pathogens and foreign particles but also lead to tissue injury. The current review compiles the past and current research in the area of inflammation with particular emphasis on oxidative stress-mediated signaling mechanisms that are involved in inflammation and tissue injury. Antioxid. Redox Signal. 20, 1126–1167. I. Introduction II. Sources of ROS and Their Regulation in Inflammation A. NADPH oxidase-derived ROS in inflammation B. Mitochondrial-derived ROS in inflammation C. Uncoupled NOS-derived ROS in inflammation D. XO-derived ROS in inflammation E. Regulation of antioxidant defense systems in inflammation III. Cell Adhesion Molecules and Leukocyte Migration Across Transendothelial Barrier A. Selectins B. Integrins C. Ig superfamily D. High endothelial venules E. Regulation of CAMs by oxidative stress IV. Structural Basis of Endothelial Integrity A. Tight junctions B. Adherens junctions C. Regulation of endothelial junctional proteins and associated cytoskeleton by oxidative stress 1. Regulation of TJs by oxidative stress 2. Regulation of AJs by oxidative stress 3. Regulation of actin cytoskeleton by oxidative stress V. Signaling Mechanisms of Endothelial Barrier Disruption by Oxidative Stress A. Altered intracellular Ca²⁺ regulation B. Myosin light chain kinase C. The Ras superfamily of GTPases D. PKCs E. Toll-like receptors VI. Oxidative Stress and Tissue Injury A. Extrinsic pathways of cell death and regulation by ROS B. Intrinsic pathways of cell death and regulation by ROS VII. Conclusion and Future Remarks