Nononcogenic pulmonary diseases are the third leading cause of death in the US and are a major factor in morbidity and disability. Pulmonary cancer is the leading cause of cancer-related deaths in both males and females. Although cigarette smoking is a major etiologic factor in these diseases, exposure to chemicals in the work place and in the environment are likely important as well. Numerous studies in laboratory animals have demonstrated the importance of the lung as a target for both inhaled and ingested environmental chemicals. One class of these toxic chemicals, the naphthalenes, are potentially important both because they result in a well defined injury to bronchiolar epithelial cells and because humans are exposed from a variety of sources. The current proposal builds on our knowledge of the metabolic activation of these agents and uses experimental approaches that have been established and validated over the past 10 years to address the following issues: 1) what molecular interactions occur subsequent to the generation of electrophiles which alter cellular homeostasis? 2) what cellular alterations occur during the repair of the initial injury and how are these modified after multiple exposures to result in tolerance? and 3) does the liver play a quantitatively important role in the generation of reactive metabolites which reach the lung via the circulation?. Recent work demonstrating the covalent binding of reactive naphthalene and 1-nitronaphthalene metabolites to actin combined with high resolution micrographs showing that membrane blabbing is a prominent event occurring prior to target cell death suggests that alterations in the cytoskeleton may be critical events in cytotoxicity. in vivo and in vitro approaches in susceptibility and nonsusceptible rodent models will be used to determine the importance of specific adducts and changes in cellular sulfhydryl levels, ATP and cytoskeleton in naphthalene toxicity. This work will use parent compound and putative toxic metabolites in lung tissue from rodents, Rhesus macaques and humans to determine whether cellular responses are species specific. Finally, these studies will provide a detailed analysis of the cellular and metabolic changes that occur in the lung during the processes of injury and repair. These studies are expected to provide improved mechanistic information regarding the interactions of chemicals with the lung. This information will provide a better basis for the extrapolation of data obtained in rodents to the human and will aid in understanding the various genetic and environmental factors which alter the (incomplete statement).
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