Potential Mechanism of Emphysema: α1-Proteinase Inhibitor Recovered from Lungs of Cigarette Smokers Contains Oxidized Methionine and Has Decreased Elastase Inhibitory Capacity

The elastase inhibitory capacity per mg of α1-proteinase inhibitor (α1PI) was measured in the bronchoalveolar lavage (BAL) fluid from 26 healthy smokers and 24 nonsmokers. Activity was decreased by 40% in smokers' BAL fluid compared to nonsmokers. This effect was demonstrable by using human neutrophil elastase as well as porcine pancreatic elastase as test enzyme (elastase, EC 3.4.21.11) and was reproducible when selected individuals in each group underwent lavage on repeated occasions. In contrast, the functional activity of α1-antichymotrypsin was not decreased in smokers' BAL fluid. Crossed antigen-antibody electrophoresis confirmed that inactivation of α1PI was responsible for the decrease in the elastase inhibitory capacity of smokers' BAL fluid. α1PI purified from smokers' BAL fluids contained methionine sulfoxide (4 mol/mol of inactive α1PI), whereas α1PI from nonsmokers' BAL fluid did not. Smokers' α1PI was indistinguishable from nonsmokers' α1PI on the basis of electrophoretic mobility, molecular weight, and immunoreactivity. Thus, oxidation of methionine residues in lung α1PI is associated with cigarette smoking. Because chemical oxidation of α1PI in vitro causes loss of its elastase inhibitory activity, the present observations suggest that methionine oxidation may also be the cause of decreased functional activity of lung α1PI in smokers. Oxidative inactivation of α1PI in the lungs of cigarette smokers may play a role in the development of pulmonary emphysema in this group.