The overall objectives of the research project are several: (1) The characterization in vitro and in vivo of a subclass of murine mast cells containing chondroitin sulfate (putative mucosal mast cells) rather than heparin proteoglycan in terms of growth factors, amino acid composition and carbohydrate structure of the peptide core of the proteoglycan, physicochemical characteristics and function of the neutral proteases of the secretory granule, development and utilization of cell-specific monoclonal antibodies for in vivo localization in normal and diseased states of the mouse, and definition of the extracellular functions of the major secretory granule constituents, namely, proteoglycan and neutral protease(s). (2) The selective oxidation of arachidonic acid by the 5-lipoxygenase pathway in cells with proinflammatory function under biologically relevant circumstances such as the introduction into the membrane of fatty acids alternative to arachidonic acid, namely eicosapentaenoic and docosahexaenoic acids from fish-enriched diets, and assessment of responses in murine mast cells and human polymorphonuclear neutrophilic leukocytes; the analysis of the selective recruitment of this pathway in human monocytes responding to particulate activators as compared to immune complexes expressing IgG; the elucidation of the mechanism(s) by which mononuclear cell-derived products, lymphokine(s) and monokine(s), augment leukotriene production in eosinophils responding to an activating stimulus; and definition of the pathway by which endogenous neutral protease of the rat mast cell initiates an activation-secretion response in this cell. (3) The demonstration of the differential distribution, cellular and subcellular, of the subclass-specific receptors for LTC4 and LTD4, in non-vascular smooth muscle and in vascular tissue, endothelial and smooth muscle, and the definition of the post-receptor biochemical events linked to these subclass-specific receptors for the sulfidopeptide leukotrienes.
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