REGULATION OF LEUKOCYTE AND VESSEL WALL CELL ADHESION

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Mononuclear leukocyte adherence to endothelium is a pivotal event in the inflammatory phase of arterial diseases such as atherosclerosis. The current model of leukocyte emigration predicts that leukocytes first adhere transiently via selectin receptors with subsequent firm adherence mediated by integrin receptors, triggered to a high avidity state by local stimuli. This proposal will examine the regulation of leukocyte adhesion, focusing on the role of selectin receptors in monocyte emigration in the arterial circulation and the regulation of beta1 integrin affinity. The following Specific Aims are proposed: 1) to determine the role of selectins in mononuclear phagocyte emigration into the arterial wall of rabbits following stimulation with chemotactic agents; 2) to determine the effect of affinity modulation by the activating beta1 MAb 8A2 in vivo; 3) to determine the adhesion pathway involved in beta1 MAb 4B5-stimulated leukocyte adherence to endothelium; 4) to examine mechanisms of high affinity mononuclear leukocyte adhesion; and 5) to determine the cytoskeletal associations of high affinity beta1 receptors.