Association between Alveolar Macrophage Plasminogen Activator Activity and Indices of Lung function in Young Cigarette Smokers

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Abstract
Recent evidence suggests that connective tissue breakdown in the human lung leading to airway obstruction and emphysema involves proteinases expressed by neutrophils and macrophages that traffic to the lungs in response to cigarette smoke. It remains unclear why only a small fraction of all cigarette smokers develop symptomatic airway obstruction. In this study, we examined indexes of inflammation and proteolytic activity in samples of bronchoalveolar lavage from young cigarette smokers and questioned whether there was any correlation between the extent of inflammation or enzymatic activity and lung function. A total of 125 apparently healthy community volunteers who currently smoked at least one pack per day were evaluated by spirometry. Seven subjects with a relatively low FEV1/FVC (% predicted) were identified and further studied by bronchoalveolar lavage. These were compared with a group of 10 smokers of similar age (mean age, 33 yr) and pack-years and higher FEV1/FVC (% predicted). Both groups showed increased accumulation of lung macrophages and neutrophils as compared to nonsmokers, but there were no differences in total cells or cellular differentials between the groups. Similarly, there were no differences in either alveolaar fluid phase elastase, antielastase, and plasminogen activator (PA) activities macrophage elastolytic activity between the groups. In contrast, there was a clear difference in macrophage plasminogen activator activity between the groups, cells from the group with a lower FEV1/FVC (% predicted) having a higher PA activity than that of macrophages from the group with higher FEV1/FVC (% predicted), i.e., 0.50 .+-. 0.16 international urokinase units/106 cells versus 0.30 .+-. 0.10 units/106 cells (p < 0.0007). A regression analysis of macrophage PA activity as a function of FEV1/FVC (% predicted) for all studied subjects showed a significant inverse correlation, p = 0.01, with a correlation coefficient of 0.58. No such correlation existed for any other paramater tested. These data indicate a previously unrecognized association between a proteolytic pathway relevant to connective tissue turnover, PA and plasmin, and lung function. Although the molecular basis for the observed finding remains to be defined, the data suggst that variability in determinants of macrophage-associated plasminogen activator activity may contribute to the variability in the rate of deterioration of lung function among cigarette smokers.