CYTOKINES, OXIDANTS, NEUTROPHILS AND LUNG INJURY

University Of Illinois At Chicago, Chicago IL

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Abstract

The production of the oxidant, H2O2, during the adhesive interaction between the activated neutrophil (PMN) and the vascular endothelium, during reoxygenation of tissues, and following TNFalpha exposure of endothelial cells is a critical event in the pathogenesis of acute lung injury. We have demonstrated that subcytolytic concentrations of H2O2 mediate intercellular adhesion molecule-1 (ICAM-1)-dependent vascular endothelial hyperadhesivity through increasing ICAM-1 mRNA synthesis and cell surface protein, thus providing a basis for PMN-mediated pulmonary vascular endothelial injury. The goal of the proposed studies is to define the mechanisms by which H2O2 signals the expression of endothelial ICAM-1 and adhesivity. Preliminary binding activity of several AP-1-like elements of the ICAM-1 promoter, including sequence repeats similar to the anti-oxidant responsive element (ARE). These studies will provide fundamental information on the mechanisms of oxidative stress-induced regulation of ICAM-1 expression in endothelial cells and the expression of endothelial cell adhesivity and PMN migration. With a better understanding of redox-regulated activation of ICAM-1 it will be possible to design rational strategies for prevention of vascular endothelial cell adhesivity and inappropriate PMN adhesion to the endothelium.