Bronchogenic carcinoma is the leading cause of cancer deaths in man. Both epidemiologic and experimental studies suggest the importance of asbestos and other minerals as cofactors in the development of this neoplasm and mesothelioma, a tumor occurring rarely in the general population but frequently in asbestos workers. Over the previous period of funding, the principal investigator has documented in tracheal bronchial epithelial cells exposed to asbestos a constellation of promoter-like effects resembling the actions of phorbol esters on target cells. These include initial cell damage, inflammatory changes and regenerative hyperplasia and metaplasia. In recent studies, the prevention of asbestos-associated cytotoxicity has been accomplished using scavengers of superoxide (02) and the hydroxyl (OH.) radical. This project is designed to test the hypothesis that active oxygen species play a role in asbestos-induced cell damage and promotion in target cells, i.e. those giving rise to bronchogenic carcinoma and mesothelioma. Specifically, we will address the questions: 1) Do specific scavengers of oxygen free radicals prevent asbestos induced damage to mesothelial cells? 2) Do mesothelial and epithelial cell types contain various scavenger enzymes (SOD, catalase, glutathione peroxidase) and is the activity of endogenous SOD altered after exposure of cells to asbestos? 3) Can administration of exogenous scavengers of oxygen free radicals prevent fiber-associated hyperplasis, squamous metaplasia and inflammation in tracheal (and mesothelial) organ cultures and grafts? 4) Does asbestos cause release of OH., H202 and 02 from both epithelial and mesothelial cells? and 5) is actual fiber-cell contact necessary for generation of oxygen free radicals? The importance of mineral chemistry, size and shape in the causation of biological responses will be addressed by using two types of asbestos (crocidolite and chrysotile) in comparison with their nonfibrous analogs (riebeckite and antigorite, respectively). Sized preparations (i.e. long (greater than 10Mu) vs short (less than 2Mu) of chrysotile also will be assessed. In addition glass particles will be included in experiments as an example of an amorphous, non-carcinogenic dust. Elucidation of the properties of minerals which are important in tumor promotion is intrinsic to understanding the process of multi-stage carcinogenesis in lung. The results of this proposal will provide a mechanistic framework for preventive and therapeutic approaches using scavengers of oxygen free radicals in man.
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