Macrophages play a critical role in host defense and inflammatory diseases through their ability to function as phagocytic and secretory cells. During inflammation, macrophages secrete substances which are involved in both promoting tissue damage and also in aiding in the repair process. Different soluble and phagocytosable stimuli are able to selectively induce the synthesis and secretion of such macrophage products, and may thus contribute to different sequelae in the inflammatory process. A complex series of regulatory mechanisms is implied. The objective of this proposal is to identify lipid mediators involved in the synthesis and secretion from stimulated macrophages of four representative products; a lysosomal hydrolase, C3, collagenase and a growth factor for fibroblasts. Stimulation of macrophages is accompanied by phospholipid turnover and the release of arachidonic acid metabolite, presumably initiated by activation of phospholipases A2 and/or C. We suggest that products of this activation are involved in regulating synthesis and secretion of the macrophage products. Since the type of products secreted depends on the nature of the stimulus, we predict that specific lipid metabolites will be formed in response to specific stimuli. The effect of the stimuli on the following phenomena will be studied (1) the release of arachidonic acid and conversion to lipoxygenase and cyclooxygenase products (2) the turnover of phospholipids and production of diacylglycerols, phosphatidic acid and lysophospholipids and (3) the modulation of phospholipase A2 and C activities. The effect of exogenous phospholipases and lipid metabolites on synthesis and secretion of specific macrophage products will be tested. We will also investigate if multiple phospholipid pools and enzyme compartments are selectively involved in regulating macrophage secretion induced by specific stimuli. Our long term objectives involve determining the role of ligand binding to specific macrophage receptors in activating specific phospholipases and determining the mechanisms by which the lipid mediators that are formed interfaced with the protein machinery of the cell to promote the sysnthesis and secretion of specific secretory proteins.
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