In chronic diseases with inflammatory or immune components, a characteristic feature is the ongoing emigration and accumulation in tissues of mononuclear leukocytes (lymphocytes and monocytes). Despite therapy, these diseases often have a progressive course, leading to severe morbidity, even mortality. Our hypothesis is that vascular cell adhesion molecule-1 (VCAM-1) expressed on endothelium is one of the regulators of mononuclear leukocyte emigration, and thus, has a pathogenic role. VCAM-1 interacts with VLA-4, a beta1 type integrin, expressed on mononuclear leukocytes, but not neutrophils. VCAM-1 expression on vascular endothelium is upregulated in a variety of chronic inflammatory conditions, typically on postcapillary venules. However, VCAM-1 is also expressed in arteries. We have shown that in hypercholesterolemic rabbits, VCAM-1 is expressed by aortic endothelium selectively at sites of mononuclear leukocyte accumulation and foam cell lesion formation. Various aspects of VCAM-1 biology have been investigated with function- blocking monoclonal antibodies. In vivo this approach has limitations, particularly when studying chronic processes. The overall objectIve of the proposed research is to elucidate the mechanisms of VCAM-1-mediated mononuclear leukocyte emigration, and the pathogenic roles of VCAM-1 in chronic inflammatory and immune diseases. In this endeavor, defined in vitro and in vivo murine models will be utilized, including VCAM-1- deficient mice (homozygous, heterozygous, and chimeric homozygous VCAM-1 knockouts).

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National Heart, Lung, and Blood Institute (NHLBI)
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