REDUCED INTRACELLULAR OXIDATIVE-METABOLISM PROMOTES FIRM ADHESION OF HUMAN POLYMORPHONUCLEAR LEUKOCYTES TO VASCULAR ENDOTHELIUM UNDER FLOW CONDITIONS

The interaction of polymorphonuclear leukocytes (PMN) with the vascula r endothelium and their subsequent extravasation to the tissues is a k ey step during different physiological and pathological processes. In certain of these pathologies the oxygen tension becomes very low, lead ing to reduced cellular oxidative status. To evaluate the effect of lo wering the intracellular redox status in the interaction of PMN with t he endothelium, exposure to hypoxic conditions as well as treatment wi th different antioxidant agents was carried out. PMN exposure to hypox ia enhanced beta(2) integrin-dependent adhesion to intercellular adhes ion molecule-1-coated surfaces, concomitant with a decrease in the int racellular redox status of the cell. As occurs with hypoxia, treatment with antioxidants produced a decrease in the oxidation state of PMN. These agents enhanced adhesion of PMN to human umbilical vein endothel ial cells stimulated with tumor necrosis factor-alpha (TNF-alpha), and this effect was also mediated by beta(2) integrins LFA-1 and Mac-1. A dhesion studies under defined laminar flow conditions showed that the antioxidant treatment induced an enhanced adhesion mediated by beta(2) integrins with a decrease in the fraction of PMN rolling on TNF-alpha -activated endothelial cells. The up-regulated PMN adhesion was correl ated to an increase in the expression and activation of integrin Mac-1 , without loss of L-selectin surface expression. Altogether these resu lts demonstrate that a reduction in the intracellular oxidative state produces an enhanced beta(2) integrin-dependent adhesion of PMN to sti mulated endothelial cells under conditions of flow.