The increased risk of developing emphysema among individuals who smoke cigarettes and who have normal levels of α1-antitrypsin (al AT) is hypothesized to result from a decrease in the antineutrophil elastase capacity of the lower respiratory tract al AT of smokers compared with nonsmokers. To evaluate this hypothesis we compared the time-dependent kinetics of the inhibition of neutrophil elastase by lung α1AT from healthy, young cigarette smokers (n = 8) and nonsmokers (n = 12). α1-antitrypsin was purified from lavage fluid using affinity and molecular sieve chromatography, and the association rate constant (k assoc) for neutrophil elastase quantified. The k assoc of smoker plasma α1AT (9.5±0.5 × 106 M-1s) was similar to that of nonsmoker plasma (9.3±0.7 × 106 M-1, P > 0.5). In marked contrast, the k assoc of smoker lower respiratory tract α1AT was significantly lower than that of nonsmoker α1AT (6.5±0.4 × 106 M-1s-1 vs. 8.1±0.5 × 106 M-1s-1, P < 0.01). Furthermore, the smoker lower respiratory tract α1AT k assoc was significantly less than that of autologous plasma (P < 0.01). When considered in the context of the concentration of α1AT in the lower respiratory tract epithelial lining fluid, the inhibition time for neutrophil elastase of smoker lung α1AT was twofold greater than that of nonsmoker lung α1AT (smoker: 0.34±0.05 s vs. nonsmoker: 0.17±0.05 s, P < 0.01). Consequently, for concentrations of al AT in the lower respiratory tract it takes twice as long for an equivalent amount of neutrophil elastase to be inhibited in the smoker's lung compared with the nonsmokers lung. These observations support the concept that cigarette smoking is associated with a decrease in the lower respiratory tract neutrophil elastase inhibitory capacity, thus increasing the vulnerability of the lung to elastolytic destruction and thereby increasing the risk for the development of emphysema.
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