Successful wound healing requires the coordinated activities of the multiple cell types that constitute the inflammatory and reparative response to tissue injury. The identification of growth factors, cytokines, extracellular matrix components and other products present in the wound promises clinical applications that will allow active therapeutic intervention during the healing process. The rational development of these applications will require, in turn, a better understanding of the cell biology of the inflammatory cells, most specifically as it relates to its modulation by conditions peculiar to the wound environment. Work in this laboratory has demonstrated that a prominent feature of healing wounds is a decreased extracellular arginine concentration that results, at the time of maximal macrophage/fibroblast infiltration, from the catabolism of arginine by extracellular arginase. It is the hypothesis that forms the basis for this proposal that the reduced arginine content of wounds is necessary and beneficial for repair and a prime modulator of phenotypic expression by inflammatory cells. This is so because a low local arginine concentration prevents the expression of a different arginine-catabolizing enzyme, nitric oxide synthase (NOS), by the same inflammatory cells. NOS is a """"""""forbidden pathway"""""""" in healing wounds because its expression results in the generation of products that suppress cell functions relevant to repair, (i.e.: phagocytosis by macrophages, fibroblast proliferation) and ultimately mediate cell death. To test this hypothesis, the Specific Aims of this proposal are designed to: define the functional phenotype of macrophages obtained from experimental wounds in the rat; evaluate the impact of altered arginine availability, wound fluids and extracellular matrix components on the maintenance of this phenotype; establish the relevance of these extracellular components to the development of a """"""""wound phenotype"""""""" by bone marrow-derived monocytes/macrophages; investigate the role of arginine in the regulation of fibroblast physiology and macrophage/fibroblast interactions and, finally, determine the mechanisms of cell injury and death associated with the expression of NOS.
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