Human Neutrophil Elastase and Elastase/Alpha1-Antiprotease Complex in Cystic Fibrosis Comparison with Interstitial Lung Disease and Evaluation of the Effect of Intravenously Administered Antibiotic Therapy1-3



Chronic, progressive endobronchial infection is associated with gradual loss of pulmonary function and is the major cause of morbidity and mortality in cystic fibrosis (CF) (1). The predominant pathogen causing pulmonary infection in patients with CF is Pseudomonas aeruginosa. Once colonization with R aeruginosa occurs, clearance of this pathogen from the air spaces of the lower respiratory tract is virtually impossible despite intensive intravenously administered antipseudomonal antibiotic therapy. R aeruginosa produces a number of extracellular virulence factors, including elastase and alkaline protease, but a specific immune response appears to neutralize these bacterial proteases in most patients with CF (2). The host inflammatory response to the presence of R aeruginosa in the lower respiratory tract, however, may cause a considerable portion of the extracellular matrix damage and lung destruction in CF. In CF, neutrophils are thought to release lysosome-derived proteases as they attempt to engulf microcolonies of R aeruginosa (3). Neutrophils are capable of releasing oxygen metabolites either directly via a membrane-associated NADPH oxidase or indirectly via the release of myeloperoxidase, an enzyme that can produce hypochlorous acid and chlorinated amine compounds from H 20 2 and chloride (4, 5). In addition to the generation of oxidants, neutrophils release a variety of proteolytic enzymes. The serine protease, neutrophil elastase (NE), is quantitatively the major protease in neutrophil granules (6) and is capable of hydrolyzing all the major connective tissue proteins that make up the lung matrix. BAL analysis in CF has revealed a marked influx of polymorphonuclear 580

SUMMARY In cystic fibrosis (CF), extracellular lung matrix is progressively damaged, neutrophils invade the air spaces, and activated neutrophlls may release large amounts of neutrophil elastase (NE). Although a,-antiprotease (a,-AP) binds and inactivates NE and Is the major antlelastase of the lower respiratory tract, antielastase defenses may be overwhelmed in CF,leading to progressive lung damage. To determine whether the ability of a,-APto neutralize NE is Impaired in CF,we compared NE activity in bronchoalveolar lavage (BAL) fluid and human neutrophil elastaselcl..-antlprotease (NE/a,-AP) complex in both BAL fluid and peripheral blood serum from patients with CF, normal volunteers, and patients with Interstitial lung disease. We detected a considerable amount of NE activity in SAL fluid from all but one patient with CF but none In that from normal volunteers or from patients with interstitial lung disease. Although in interstitial lung disease there was a significant correlation between increased NE/

alpha 1-antiprotease complex in cystic fibrosis. Comparison with interstitial lung disease and evaluation of the effect of intravenously administered antibiotic therapy.

In cystic fibrosis (CF), extracellular lung matrix is progressively damaged, neutrophils invade the air spaces, and activated neutrophils may release ...
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