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 Therapy

Abstract

In cystic fibrosis (CF), extracellular lung matrix is progressively damaged, neutrophils invade the air spaces, and activated neutrophils may release large amounts of neutrophil elastase (NE). Although alpha 1-antiprotease (alpha 1-AP) binds and inactivates NE and is the major antielastase of the lower respiratory tract, antielastase defenses may be overwhelmed in CF, leading to progressive lung damage. To determine whether the ability of alpha 1-AP to neutralize NE is impaired in CF, we compared NE activity in bronchoalveolar lavage (BAL) fluid and human neutrophil elastase/alpha 1-antiprotease (NE/alpha 1-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 BAL 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-AP complex in BAL or peripheral blood and the degree of neutrophil influx, NE/alpha 1-AP complex was disproportionately low in CF BAL compared with significantly elevated values in serum. These data suggest that in CF, alpha 1-AP-mediated defense against free NE in the lower respiratory tract is significantly impaired, and high levels of uncomplexed, enzymatically active, NE are present in CF respiratory secretions. To determine whether intravenously administered antipseudomonal antibiotic therapy for exacerbations of CF lung disease diminished the amount of free NE in respiratory secretions, we used BAL to investigate the effect of such therapy on neutrophils and NE in patients with CF colonized with pseudomonads.(ABSTRACT TRUNCATED AT 250 WORDS)

Breath isoprene during acute respiratory exacerbation in cystic fibrosis

“…To minimize variations in concentration due to rate and depth of breathing, breath isoprene was calculated as a production rate in mass eliminated per kg of body mass per unit of time rather than as an absolute concentration. This does not resolve the problem encountered in the present study that breath isoprene decreased during the period of maximum oxidative stress and increased towards normal following treatment which would be expected to diminish oxidative stress [28]. This raises the possibility that isoprene either does not track, or is indirectly related to, oxidative stress.…”

Neutrophil Elastase Represses IL-8/CXCL8 Synthesis in Human Airway Smooth Muscle Cells through Induction of NF-κB Repressing Factor

“…Importantly, NE also attenuates the secretion of IL-8/CXCL8 stimulated by TNF-␣, indicating the concomitant release of NE from recruited polymorphonuclear cell (PMN) to hASM may modify the cytokine-induced IL-8/XCXL8 production under inflammatory conditions. The activity of NE (0.5 g/ml or 0.33 U/ml) used in most of our experiment is ϳ1/10 as much as in sputum from cystic fibrosis patients with clinical exacerbations (3 U/ml, airway PMN burden 1.3 ϫ 10 6 /ml) (40,41) and is similar to that from stable cystic fibrosis patients (airway PMN burden 1.9 ϫ 10 5 /ml) (41). Thus, we found a previous undiscovered role of NE in the modulation of IL-8/CXCL8 expression specifically in hASM.…”

Sputum Biomarkers of Inflammation in Cystic Fibrosis Lung Disease

“…The most common direct method is by performing bronchoscopy with bronchoalveolar lavage (BAL) or bronchial washing. Much of what has been learned about infection and inflammation in the CF lung has been through the use of BAL (14,29,45,(55)(56)(57)(58)(59)(60)(61)(62) and much of the experience evaluating the "biologic efficacy" of therapeutics in CF has been through the use of BAL (46,(63)(64)(65)(66)(67)(68)(69)(70)(71). Thus, BAL and bronchial washing are considered by most investigators and clinicians to be the gold standard for assessing infection and inflammation in the CF lung.…”

“…However, a systemic marker may not be sensitive enough to detect a meaningful change in lung disease, given that the inflammatory response to infection in the CF lung is largely confined to the lung. Assessments in blood have included antibodies to Pseudomonas aeruginosa (81)(82)(83) or products of inflammation (84), neutrophil elastase ␣ 1 -antiprotease complexes (63,85), C-reactive protein (CRP) (85,86), and various cytokines from serum or plasma (27,(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97), and blood cells themselves (32,33,(98)(99)(100)(101)(102)(103). C-reactive protein is gaining increased recognition as a marker of inflammation for other diseases, but in CF, it is widely variable due to transient increases during pulmonary exacerbations (104,105).…”