The spectrum of granulomatous lung disease is broad, encompassing diseases caused by readily identifiable microbial agents (e.g. tuberculosis, schistosomiasis), foreign particulates (e.g. berylliosis, talcosis), and diseases in which no causative agent has been identified (e.g. Wegener's granulomatosis, sarcoidosis). Central to granuloma formation is the coordinated recruitment of mononuclear phagocytes, and in some types of lesions. T lymphocytes, into discrete anatomic foci. Intravenous infusion of particulate yeast cell wall glucan into rats results in the synchronous development of foreign body-type granulomas that are composed almost entirely of monocytes and macrophages. Monocyte chemoattractant protein-1 (MCP-1) activity is required for full development of granulomas. There is an early (1-4 hrs.) blood vessel wall-associated rise in MCP-1 and a later (6-24 hrs.) rise in MCP-1 activity which is associated with granuloma cells per se. The early rise in MCP-1 activity is temporally and anatomically associated with the transient influx of neutrophils into vessel walls (at sites of glucan embolization). Likewise, in Mycobacterium bovis (BCG) - infected mice, there is an early, transient inflex of neutrophils into sites of subsequent pulmonary granuloma formation. In contrast to glucan-induced granulomas, hypersensitivity-type M. bovis (BCG)-induced lesions contain T lymphocytes. Completed studies suggest that the recruitment of mononuclear cells into evolving lung granulomas is orchestrated in part by monocyte chemotactic beta chemokines such as MCP-1. Regulated upon Activation, Normal T-cell Expressed and presumably Secreted (RANTES), macrophage inflammatory protein 1alpha (MIP-1alpha), and MIP 1beta. We hypothesize that the early expression of these peptides within localized segments of blood vessel walls is induced by products of neutrophils (specifically, reactive oxygen intermediates (ROIs). The role of neutrophils and ROIs in the induction of beta-chemokines will be studied in vivo and in vitro. Time course and topographic analyses of beta chemokine (MCP-1, RANTES, MIP-1alpha. MIP-1beta) mRNA and protein expression during evolving glucan and M. bovis (BCG-induced pulmonary granulomatosis will be carried out by Northern and dot hybridization, in situ hybridization, and immunohistochemistry. Granuloma development and beta-chemokine expression will be examined in neutrophil-sufficient, neutrophil-depleted, and specific antioxidant-treated animals. Finally, biochemical and molecular mechanisms of neutrophil ROI-induced beta- chemokine expression will be systematically examined in isolated human endothelial cells, alveolar type II epithelial cells, and fibroblasts (vessel wall constituents). The proposed in vitro studies will focus on how ROI-dependent cellular redox status modulates the expression of beta- chemokines.
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