Our working hypothesis suggests that the relationship between a history of cigarette smoking and the development of emphysema rests on three events. First, the oxidants in cigarette smoke inactivate Alpha-1-proteinase inhibitor, the major elastase inhibitor in the lung parenchyma. Second, cigarette smoke stimulates accumulation of alveolar neutrophils and macrophages with concomitant elastase release into the alveolar space and alveolar interstitium. Third, elastin destruction is initiated, unless the oxidized, inactive elastase inhibitor can be reactivated in the lung, thus arresting elastin breakdown by inhibiting the released elastase. In order to verify the hypothesis, we will use biochemical, immunological and ultrastructural analyses of lung components from smoking and non-smoking animals. We will measure functional and oxidized (inactive) proteinase inhibitor and the effect of cigarette smoke dose and duration of smoking on active vs. inactive inhibitor in the lung. We will also analyze the effect of cigarette smoke exposure on the cell populations in the lung, with particular emphasis on elastase release. Finally, we will determine if the lung can adapt to the oxidants present in cigarette smoke by stimulating the activity of methionine-sulfoxide-peptide reductase, an enzyme known to reactivate oxidized Alpha-1-proteinase inhibitor. These studies have as long term objectives a better understanding of the response of the lung to cigarette smoke exposure, so that human emphysema can be diagnosed more rapidly and more effectively and so a more rational and efficatious therapy can be instituted.
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