Monocytes/macrophages play key roles in inflammatory and atherosclerotic processes, which in several instances proceed at extravascular tissue sites and are characterized by extensive fibrin deposition and a fibroproliferative response. Since thrombin is a potent effector of these responses, the overall hypothesis is that thrombin production at the monocyte/macrophage surface provides an important bioregulatory effector molecule at these sites. The objectives are to define the binding and kinetic parameters governing the molecular events which result in the expression of thrombin at the monocyte/macrophage surface and begin to elucidate the cellular mechanisms which regulate the expression of a procoagulant phenotype. Particular emphasis is placed on how the monocyte/macrophage surface membrane regulates prothrombinase complex assembly and function through the expression of binding sites for the cofactor factor Va and the enzyme factor Xa, and the expression of membrane-bound proteases which activate the procofactor factor Va to factor Va. The overall goal of this project is to provide a detailed understanding of how thrombin generation is effected and regulated at the monocyte surface through a series of integrally related events. The formation of thrombin at the monocyte/macrophage surface appears to be pivotal to the physiological and pathophysiological functions these cells provide as they localize to vascular and extravascular tissue sites.
Showing the most recent 10 out of 94 publications
