PATHOBIOLOGY OF MACROPHAGE-FIBRONECTIN INTERACTIONS

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Extracellular matrix proteins, including fibronectin (FN), provide an important means for modulating of cell function. During inflammation and wound healing, plasma FN (pFN) extravasates and is incorporated into fibrin gels that are thought to serve as a provisional matrix for the migration of a variety of inflammatory cells as well as keratinocytes and fibroblasts. When tested in culture, pFN modulates certain functions of mononuclear phagocytes, including, phagocytosis, migration, synthesis and secretion. This adhesive glycoprotein is synthesized by macrophages and also enhances certain activities of these cells. Fibronectin is not a single protein but comprises a group of closely related glycoproteins which arise by alternative splicing within a single gene transcript. It is now clear that different cells secrete different forms of fibronectin, however the structure of fibronectins produced by macrophages is unknown. This proposal is concerned with elucidating the structure and function of fibronectins produced by macrophages during inflammation. Preliminary evidence, obtained by in situ hybridization with domain-specific fibronectin probes, indicates that these cells modulate the forms of fibronectin produced during wound healing. Experiments are proposed, utilizing this methodology, as well as RNA mapping and immunocytochemistry, to determine if macrophages in delayed hypersensitivity reactions and granulomas also express alternatively spliced forms of fibronectin. These data provide the basis for experiments, using recombinant fibronectins, to determine if spliced domains within this protein alter specific macrophage functions. A third part of this study proposes experiments to establish culture conditions which modulate fibronectin synthesis and alternative splicing patterns. These experiments are expected to provide new insights into the functions of specific domains within fibronectin, the role that alternatively spliced forms of fibronectin and macrophages play during inflammation, and may ultimately provide the basis for therapeutic modulation of macrophage function during wound healing.