Granulomatous diseases are highly destructive tissue reactions which often involve the lungs. Clinically, pulmonary granulomatous inflammation is difficult to manage, requiring potent anti-inflammatory drugs that can compromise the patient's metabolic and immunologic integrity. This proposal will focus on the key inflammatory cell involved in these chronic immune reactions, the granuloma macrophage. A systematic study will examine the role of the macrophage in the initiation, maintenance, and resolution of hypersensitivity and foreign body-type pulmonary granulomas and to delineate the factors involved in granuloma macrophage activation and regulation. This investigation will focus on: a) the role of macrophage arachidonic acid metabolism in the induction and regulation of granuloma formation; b) the role of other cellular components in governing granuloma macrophage function; and c) the molecular mediators involved in granuloma macrophage activation and modulation. Two established models of pulmonary granulomas will be used. 1) Hypersensitivity-type pulmonary granulomas will be induced by the embolization Schistosoma mansoni eggs resulting in a highly active, T-cell mediated, lesion, and 2) foreign body-type, nonimmune granulomas will be induced by the embolization of polysaccharide bead (Sephadex). In addition to a morphologic and morphometric analysis of the developing granuloma, both types of lesions will be sequentially isolated and dispersed to examine dynamic changes in macrophage function. Techniques employed to analyze granuloma macrophage functions will include: assays to monitor the toxic oxygen metabolite, superoxide anion; radioimmunoassays to measure prostaglandin levels; high pressure liquid chromatography (HPLC) analysis of arachidonic acid metabolism to cyclooxygenase and lipoxygenase products; and immunofluorescence to detect surface Ia antigens by flow cytometer and UV microscopy. This proposal places special emphasis on the importance of the macrophage arachidonic acid metabolism in pulmonary granuloma formation and should provide an understanding of its regulation at both the celluar and molecular levels. The long-range objective is to elucidate granuloma macrophage effector functions and to gain an understanding of the involvement of these cells in the pathophysiology of pulmonary granulomatous diseases. Since granuloma macrophages are undoubtedly the key cell in these dynamic immune responses, a precise understanding of their role will prove helpful in developing rational approaches to therapeutically manipulate granulomatous disease.
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