Cellular initiation of the coagulation protease cascade participates in various biological responses including vascular diseases, athero-thrombotic lesions, immune and inflammatory reactions. Among cells implicated in the immune response, circulating blood monocytes efficiently initiate coagulation via surface expression of tissue factor and assembly of a proteolytic binary complex with factor VIIa. Monocytes also exhibits a broad range of molecular interactions with other cells, plasma, and extracellular matrix proteins. These mechanisms of cell:cell and cell:ligands communication are governed and modulated by a group of highly specialized surface receptors that include Mac-1 (CD 11b/CD18), LFA-1 (CD 11a/CD18), and p150,95 (CD 11c/CD18). These are leukocyte-restricted members of the superfamily of integrin adhesive receptors. Recent studies have shown that Mac-1, after appropriate signalling, can coordinate a molecular assembly of coagulation proteins fibrinogen and factor X. Because on monocytes this is followed by activation of X and rapid initiation of a procoagulant response, the hypothesis of an additional biological function of this receptor is postulated. The regions of Mac-1, fibrinogen and factor X implicated in this supramolecular interaction will be identified with synthetic peptides, monoclonal antibodies of defined recognition, limited proteolysis and ligand-receptor chemical cross-linking studies. The dynamic modulation of Mac-1 receptor function will be characterized in kinetic binding studies and early events of signal transduction in response to various agonists. Finally, the pathway of Mac- 1- activation of X will be characterized in the context of the monocyte- mediated process of fibrin formation. The overall project is designed to provide insights into a newly described function of Mac-1, inducible by physiologic agonists, that might collaboratively or alternatively contribute to the mechanism of fibrin deposition, in vivo.
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