Inhalation of silicate dusts can result in a wide variety of lung diseases including pneumoconiosis. The mechanism of toxicity is not known. I hypothesize that lung disease following mineral dust inhalation results from the coordination of iron by surface silanol groups with the subsequent production of oxidants via the Fenton reaction. Utilizing silica, crocidolite, kaolinite, talc, and diamond dust (control), we will investigate determinants of silicato-iron complex formation including cation exchange capacity and surface silanol density of the dusts. The critical stability constant for the coordination of ferric ion by silicates will be quantified and the capacity of the dusts to employ body sources of iron (mono- and diferric transferrin) will be examined. Each of the five dusts will then be iron loaded, wetted with saline, and treated with deferoxamine to vary concentrations of surface complexed iron. Release of tumor necrosis factor and interleukin 1 (cytokines of importance in the development of pneumoconiosis) by cultured rat alveolar macrophages following dust exposure will be investigated and associations with surface iron evaluated. Correlations between coordinated iron, oxidant production, and lung damage in an in vivo model of pneumoconiosis will then be pursued. Immediately before and at regular intervals after (every 30 days for 6 months) intratracheal injection of the dust, iron concentrations, indices of oxidant production, and measures of lung damage in the lung (including hydroxyproline and a histologic index of interstitial fibrosis) are to be quantified. Finally, an in vitro test of in vivo fibrotic potential is to be examined. The capacity of the iron saturated silicate to generate oxidants in a chemical system should predict which dusts will produce pneumoconiosis in vivo. Ten characterized (particle size, surface potential, and surface area) silicates will be tested for iron adsorption, oxidant production, and fibrotic response at 6 months after intratracheal introduction. This proposal will apply coordination and surface geochemistry to further understanding of mechanisms of lung injury and will also strongly contribute to the development of a therapy for pneumoconiosis.
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