NEUTROPHIL MEDIATORS, PSEUDOMONAS, AND PULMONARY DYSFUNCTION IN CYSTIC-FIBROSIS

Proteolytic enzymes derived from inflammatory cells or Pseudomonas aer uginosa may destroy lung matrix in cystic fibrosis (CF). Antielastases appear to be overwhelmed by large amounts of free neutrophil elastase (NE) activity in lower respiratory tract secretions, and proteolytic or oxidant stress is thought to account for such deficiency. The purpo se of this study was to measure NE and myeloperoxidase activity in bro nchoalveolar lavage fluid (BAL) from patients with CF and to correlate levels of these mediators with the degree of airflow obstruction and density of P. aeruginosa in BAL. We measured NE activity in BAL fluid from 14 patients with respiratory exacerbations of CF. NE complexed wi th alpha1-antiprotease in peripheral blood was measured in 13 of the 1 4 patients subjected to BAL and in 21 additional patients who did not undergo BAL. Because oxidants generated by myeloperoxidase may contrib ute to increased elastase activity via inactivation of alpha1-antiprot ease, myeloperoxidase activity in BAL was also measured. We found that elastase activity in BAL correlated significantly with the ratio of f orced expiratory volume in 1 second to forced vital capacity (FEV1/FVC ratio) (r = 0.80, p < 0.001) and FEV1 percent predicted (r = - 0.62, p 0.02). Myeloperoxidase activity also significantly correlated with a irflow obstruction (FEV1/FVC ratio, r = 0.70, p = 0.005; FEV1 percent predicted, r = - 0.52, p = 0.05). However, the degree of airflow obstr uction, NE activity, myeloperoxidase activity, or total neutrophils in BAL did not correlate with the density of P. aeruginosa (CFU/ml) or t otal pathogen burden in BAL fluid. We conclude that the severity of th e host inflammatory response and the release of neutrophil mediators i nto the lower respiratory tract are of prime importance in the progres sive airflow obstruction that characterizes lung disease in CF. Althou gh P. aeruginosa is an important stimulus for lower respiratory tract inflammation in CF, its density in BAL fluid does not appear to correl ate with the degree of inflammation as reflected by neutrophil mediato rs in BAL or with the degree of pulmonary dysfunction (FEV1/FVC ratio or FEV1 percent predicted). These data suggest that strategies that de press or neutralize the host inflammatory response in CF may be of equ al or greater importance than antibacterial chemotherapy for the preve ntion of progressive lung destruction in CF.