MESOTHELIAL CELL ACTIVATION IN ASBESTOS INDUCED INJURY

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Pleural fibrosis is the most common toxicologic manifestation of human asbestos-induced disease. Furthermore, asbestos-related pleural fibrosis has important clinical significance, since it can cause pulmonary restriction and is a marker of increased risk for asbestos-related cancers. However, the mechanisms governing asbestos-mediated pleural fibrosis are poorly understood, and there also has been a long-standing controversy regarding the potential of different commercial types of asbestos to cause pleural injury. In this proposal, it is postulated that inhaled asbestos fibers are phagocytized by pleural mesothelial cells and pleural macrophages, which induces upregulation of certain cytokines, chemotactic proteins and adhesion molecules by these cells. To address this hypothesis, the proposed research will have two components: one will entail the use of an animal inhalational model of asbestos exposure and the other will utilize a number of in vitro studies. The Specific Aims are: (1) to determine, using a rat inhalational model, whether a fiber gradient exists with respect to the phagocytosis of amphibole (crocidolite) versus serpentine (chrysotile) asbestos fibers by pleural mesothelial cells and pleural macrophages, and to determine whether asbestos inhalation enhances pleural macrophage recruitment and activation; (2) to determine whether in vitro exposure of rat pleural mesothelial cells to asbestos fibers induces upregulation of the adhesion proteins, fibronectin and ICAM-I, and the cytokines, interleukin-1, (IL- 1), platelet derived growth factor (PDGF), transforming growth factor-beta (TGF-beta) and monocyte chemoattractant protein-1 (MCP-1); (3) to determine whether in vitro exposure of rat pleural macrophages to asbestos fibers induces upregulation of the adhesion protein, LFA-1, the pro- inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and MCP-1, and the fibroblast growth factors, fibronectin, IL-1, TGF-beta and PDGF; (4) to determine whether in vitro asbestos exposure enhances the adherence of rat pleural macrophages to rat pleural mesothelial cells in the context of adhesion molecule expression. For the in vitro studies, comparisons will be made between the effects of chrysotile and crocidolite asbestos and those of non-fibrogenic control particulates, MMVF11 fibers and carbonyl iron particles. For the inhalational toxicology studies, comparisons will be made between the effects of both types of asbestos inhalation and the effects of sham exposure. The proposed studies have important significance for the pathogenesis of asbestos-induced pleural injury.