It is well known that asbestos and silica are serious health hazards. However, not enough information is known about the mechanism of actions and the biochemical and physiological effects of these dusts. Experimental models of asbestos and silica exposure suggest that the alveolar macrophage is the most important component of the resulting inflammatory response from its earliest stages onward. Therefore, the goal of the proposed research will be to better describe the mechanisms of interaction of asbestos (chrysotile and crocidolite) and silica (quartz) with alveolar macrophages. The primary aims will be to 1) determine how asbestos stimulates superoxide anion production, and 2) characterize the effects of asbestos and silica on agonist stimulated superoxide anion production and arachidonic acid metabolism, both of which could be used to explain the resulting fibrosis from in vivo asbestos and silica exposure. The primary hypothesis that will be tested is that the effects of asbestos and silica are mediated via a specific metabolic alteration (calcium metabolism and/or phosphatidyl inositol cycle activity) which could result in altered alveolar macrophage metabolic activity during normal physiologic activation. In order to test this hypothesis, the effects of in vitro incubation of the dusts (below cytotoxic doses) on guinea pig alveolar macrophage superoxide anion production and arachidonic acid metabolism will be fully characterized. These studies will also include analysis (using radioactive and fluorescently labelled lectins) of binding of one or more of the dusts to specific glycoproteins on the macrophage plasma membrane. Second, lipid peroxidation under similar conditions will be quantitated and the physiologic effects of altering lipid peroxidation will be measured in order to determine whether there is any connection between lipid peroxidation and action of the dusts. Third, the effects of asbestos and silica on calcium metabolism and phosphatidyl inositol cycle activity will be measured in order to determine the specificity of action of the dusts and evaluate the probability that all of the effects of asbestos and silica may be explained though effects on this pathway.
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