Cigarette smoking is the major cause of pulmonary emphysema, yet the question remains of why only a small portion of smokers develop clinically-apparent emphysema. To address this issue, we have compared the levels of proteases and anti-proteases in bronchoalveolar lavage (BAL), together with the function of alveolar macrophages between asymptomatic community-based older volunteers who had emphysema detected by high resolution CT scans and those who had a similar smoking history but did not have emphysema. In a series of experiments we have found the following. (1) The concentration of the neutrophil elastase-α1 protease inhibitor complex (NE-α1PI) was significantly elevated in the BAL fluid of subjects with subclinical emphysema. (2) More NE-α1PI was released from cultured alveolar macrophages in emphysematous smokers, which supports the idea that more NE is taken up by macrophages in those subjects. (3) The level of elastin-derived peptides in the BAL fluid correlated with the level of NE-α1PI and was significantly higher in current smokers than former smokers. (4) The immunological level of cathepsin L, another potential protease candidate causing emphysema which originates mainly from macrophages, was significantly higher in the subjects with subclinical emphysema, but, when subjects aged < 60 yrs were chosen for comparison, there was no difference between the two groups for cathepsin L. However, the difference between these groups remained for NE-α1PI. (5) The levels of human neutrophil lipocalin and two matrix metalloproteinases, gelatinase B (MMP-9) and neutrophil collagenase (MMP-8), were also significantly elevated in the BAL fluid from subjects with subclinical emphysema compared to smokers without emphysema. (6) Among the several neutrophil and/or monocyte chemoattractants, only the level of IL-8 in the BAL fluid had a strong positive correlation with NE-α1PI, and was significantly elevated in the subjects with subclinical emphysema. These data support the notion that neutrophils and a neutrophil chemoattractant, IL-8, appear to be crucial in the early development of emphysema and provide a clue to solving the question of why only a small portion of smokers develop clinically-apparent emphysema.
