Pulmonary granulomatous diseases are often highly destructive and extremely difficult to manage, requiring potent anti-inflammatory drugs that can compromise the patient's immunologic and metabolic integrity. In order to elucidate the factors dictating the induction and maintenance of these lesions, this proposal will examine the production/interaction of key chemical signals by peripheral blood monocytes, alveolar macrophages and granuloma macrophages from animals with hypersensitivity and foreign body-type lung granulomas. The sequential production of interleukin-1 (IL-1), fibroblast growth factor, arachidonate metabolites, and tumor necrosis factor (TNF) will be analyzed and related to local inflammatory events and associated systemic changes. In addition to the above monocyte/macrophage-derived mediators, a concomitant assessment of serum for the acute phase protein serum amyloid-P, and cell-free bronchoalveolar lavage fluid, for interleukins, TNF, and arachidonic acid metabolites, will be made. The in vivo relevance of IL-1 and TNF will be addressed by a) depleting IL-1 and TNF with specific antibodies at various times during granuloma development and, b) using IL-1 and TNF coated beads as granuloma-inducing agents. Two established models of pulmonary granulomas will be employed: hypersensitivity-type pulmonary granuloma will be induced by embolization of Schistosoma mansoni eggs resulting in a highly active, T-cell mediated lesion; and foreign body-type granulomas will be induced by the embolization of Sephadex beads. Techniques and methodologies employed throughout this proposal include: lymphocyte and fibroblast proliferative assays, bioassays for TNF, radioimmunoassays, and high pressure liquid chromatography. A unique aspect of this proposal is the implementation of these models to evaluate approaches to therapeutic management of pulmonary granulomatous diseases. The therapeutic usefulness of specific protocols will be assessed by examining morphologic/morphometric alterations at the local lesion level as well as molecular mediator changes at the cellular level. This study will provide important knowledge regarding 1) the role of monocyte/macrophage mediators in granuloma development, 2) parameters which reflect active granulomatous inflammation and 3) the mechanism and efficacy of pharmacologic manipulation of granuloma formation.
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