PATHOBIOLOGY OF MACROPHAGE - FIBRONECTIN INTERACTIONS

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Mononuclear phagocytes play an important role in many pathological processes involving fibrin, and are ubiquitous cells in chronic inflammation. Numerous and intimate interactions occur between these cells and the coagulation system. Macrophages bind coagulation factors, promote clotting reactions, bind and degrade fibrin, and bind plasma proteins though to modulate these interactions. One such plasma protein is fibronectin which has discrete binding sites that are specific for ligands including fibrin, Factor XIIIa and cells. This adhesive glycoprotein is synthesized by marcophages and also enhances certain phagocytic activities of these cells. This proposal is concerned with the molecular basis for macrophage-fibronectin interactions, and particularly the cell surface molecule(s) responsible for binding this protein. Several lines of evidence suggest that the receptor for fibronectin is different than that of other cells (e.g., fibroblasts) and the major aim of research proposed is to identify this receptor in mononuclear phagocytes. Three independent but complementary approaches are proposed, including the fractionation of cells by affinity chromatography, the generation of anti-macrophage monoclonal antibodies, and the use of chemical cross-linking reagents. The properties of the receptor will be examined in detail using these methods in conjunction with phagosome isolation procedures. Experiments are proposed to study the properties of this cell surface receptor, to determine its relatedness to the fibroblast receptor, and to study it in monocytes, macrophages and cell lines. These experiments are expected to provide new insights into interactions between fibronectin and mononuclear phagocytes and provide a basis for understanding this interaction in pathological processes.