Oxidants Spontaneously Released by Alveolar Macrophages

Current concepts relating to the pathogenesis of emphysema associated with cigarette smoking is that an imbalance exists within the lower respiratory tract between neutrophil elastase and the local anti-neutrophil elastase screen, enabling uninhibited neutrophil elastase to destroy the alveolar structures over time. The possible role of alveolar macrophages in contributing to this imbalance was investigated by evaluating the ability of cigarette smokers' alveolar macrophages to inactivate alpha 1-antitrypsin (alAT), the major anti-neutrophil elastase of the human lower respiratory tract. In vitro, alveolar macrophages of smokers spontaneously released 2.5-fold more superoxide anion and eightfold more H202 than macrophages of nonsmokers (P < 0.01, both comparisons). Using a model system that reproduced the relative amounts of alveolar macrophages and aIAT found in the epithelial lining fluid of the lower respiratory tract, we observed that smokers' macrophages caused a 60±5% reduction in the ability of alAT to inhibit neutrophil elastase. In marked contrast, under the same conditions, nonsmokers' macrophages had no effect upon the anti-neutrophil elastase function of alAT. Addition of superoxide dismutase, catalase, mannitol, and methionine prevented inactivation of alAT by smokers' macrophages, implying that the release of oxidants mediated the inactivation of alAT. In addition, by utilizing a recombinant DNA produced modified form ofalAT containing an active site substitution (met" -* val), the inactivation of alAT by smokers' alveolar macrophages was prevented, suggesting that the smokers' macrophages inactivate alAT by oxidizing the active site of the alAT molecule. These results suggest that in cigarette smokers, the alveolar macrophage can modulate the activity of alAT as an inhibitor of neutrophil elastase and thus play a role in the pathogenesis of emphysema associated with cigarette smoking.