Platelet dysfunction is a prominent feature of inflammatory bowel diseases (IBD) as evidenced by thrombocytosis, platelets that circulate in an activated state, an increased risk of systemic thromboembolism, and the detection of intravascular platelet aggregates in mucosal biopsies of patients with IBD. Despite the evidence suggesting that platelets may contribute to the pathogenesis of IBD, relatively little is known about the nature, time-course and mechanisms underlying the accumulation of platelets in the chronically inflamed intestine. The work outlined in this application will focus on defining the mechanisms that underlie the recruitment of activated platelets in the inflamed mouse colon and will address the contribution of platelets to the tissue injury and overall disease activity in two established experimental models (DSS and CD4+CD45RBhigh T-cell transfer) of murine colitis. Intravital fluorescence microscopy and the dual radio labelled monoclonal antibody technique will be used to test our central hypothesis that experimental colitis is associated with platelet-endothelial cell adhesion, which enhances endothelial cell adhesion molecule (CAM) expression through the engagement of CD40-ligand (CD154) on platelets with CD40 on endothelial cells. The increased endothelial CAM expression promotes the recruitment of leukocytes, which, in concert with the recruited platelets, lead to endothelial cell dysfunction and increased colitic disease activity.
Four specific aims are proposed: 1) to define the temporal relationship between activation of circulating platelets, platelet-endothelial cell (P/E) adhesion and the progression of disease activity in experimental colitis, 2) to determine which adhesion molecules mediate the platelet adhesion in experimental colitis and whether platelets bind to the venular wall through an interaction with leukocytes that are already adherent to venular endothelium, 3) to determine whether platelet adhesion contributes to the increased endothelial CAM expression and leukocyte-endothelial cell adhesion associated with colonic inflammation, and to define the contribution of CD40-CD154 (CD40L) interactions to the P/E adhesion dependent expression of endothelial CAMs, and 4) to define the contribution of platelet adhesion and CD40 CD40L interactions to the endothelial cell dysfunction (increased vascular permeability, oxidant stress) and progression of disease activity in murine models of colitis. The proposed work should result in a better understanding of the nature and contribution of platelet activation and adhesion to the pathogenesis of IBD. ? ? ?
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