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

K. C. Meyer, J. R. Lewandoski, J. J. Zimmerman, D. Nunley, William Calhoun, G. A. Dopico

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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 α1-antiprotease (α1-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 α1-AP to neutralize NE is impaired in CF, we compared NE activity in bronchoalveolar lavage (BAL) fluid and human neutrophil elastase/α1-antiprotease (NE/α1-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/α1-AP complex in BAL or peripheral blood and the degree of neutrophil influx, NE/α1-AP complex was disproportionately low in CF BAL compared with significantly elevated values in serum. These data suggest that in CF, α1-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. After 2 wk of intravenously administered antipseudomonal antibiotic therapy, free NE activity significantly diminished in BAL fluid (204 ± 102 versus 89 ± 46 nmol peptide hydrolyzed/min/ml BAL fluid; p = 0.02). Serum NE/α1-AP complex also declined significantly in convalescent specimens (393 ± 58 versus 183 ± 24 μg/L; p = 0.0006) and approached levels near those of normal volunteer subjects (116 ± 10 μg/L), although convalescent levels were still significantly increased above levels for normal volunteers (p = 0.04). Intensive antibiotic therapy diminished free NE in BAL fluid, but a considerable amount of NE activity remained in lower respiratory tract secretions after such therapy. Our data show that although antibiotics are of some benefit in reducing specific markers of pulmonary inflammation in CF, other therapies such as the administration of antiproteases also may prove useful in treating patients with CF by modulating progressive, protease-mediated lung damage.

Original languageEnglish (US)
Pages (from-to)580-585
Number of pages6
JournalAmerican Review of Respiratory Disease
Volume144
Issue number3 I
StatePublished - 1991
Externally publishedYes

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Leukocyte Elastase
Pancreatic Elastase
Interstitial Lung Diseases
Protease Inhibitors
Cystic Fibrosis
Anti-Bacterial Agents
Bronchoalveolar Lavage Fluid
Therapeutics
Healthy Volunteers
Neutrophils
Bronchoalveolar Lavage
Respiratory System
Lung
Serum

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

@article{8cfc84dca20d43289f7f091767ebe992,
title = "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 α1-antiprotease (α1-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 α1-AP to neutralize NE is impaired in CF, we compared NE activity in bronchoalveolar lavage (BAL) fluid and human neutrophil elastase/α1-antiprotease (NE/α1-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/α1-AP complex in BAL or peripheral blood and the degree of neutrophil influx, NE/α1-AP complex was disproportionately low in CF BAL compared with significantly elevated values in serum. These data suggest that in CF, α1-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. After 2 wk of intravenously administered antipseudomonal antibiotic therapy, free NE activity significantly diminished in BAL fluid (204 ± 102 versus 89 ± 46 nmol peptide hydrolyzed/min/ml BAL fluid; p = 0.02). Serum NE/α1-AP complex also declined significantly in convalescent specimens (393 ± 58 versus 183 ± 24 μg/L; p = 0.0006) and approached levels near those of normal volunteer subjects (116 ± 10 μg/L), although convalescent levels were still significantly increased above levels for normal volunteers (p = 0.04). Intensive antibiotic therapy diminished free NE in BAL fluid, but a considerable amount of NE activity remained in lower respiratory tract secretions after such therapy. Our data show that although antibiotics are of some benefit in reducing specific markers of pulmonary inflammation in CF, other therapies such as the administration of antiproteases also may prove useful in treating patients with CF by modulating progressive, protease-mediated lung damage.",
author = "Meyer, {K. C.} and Lewandoski, {J. R.} and Zimmerman, {J. J.} and D. Nunley and William Calhoun and Dopico, {G. A.}",
year = "1991",
language = "English (US)",
volume = "144",
pages = "580--585",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "3 I",

}

TY - JOUR

T1 - Human neutrophil elastase and elastase/alpha1-antiprotease complex in cystic fibrosis

T2 - Comparison with interstitial lung disease and evaluation of the effect of intravenously administered antibiotic therapy

AU - Meyer, K. C.

AU - Lewandoski, J. R.

AU - Zimmerman, J. J.

AU - Nunley, D.

AU - Calhoun, William

AU - Dopico, G. A.

PY - 1991

Y1 - 1991

N2 - 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 α1-antiprotease (α1-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 α1-AP to neutralize NE is impaired in CF, we compared NE activity in bronchoalveolar lavage (BAL) fluid and human neutrophil elastase/α1-antiprotease (NE/α1-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/α1-AP complex in BAL or peripheral blood and the degree of neutrophil influx, NE/α1-AP complex was disproportionately low in CF BAL compared with significantly elevated values in serum. These data suggest that in CF, α1-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. After 2 wk of intravenously administered antipseudomonal antibiotic therapy, free NE activity significantly diminished in BAL fluid (204 ± 102 versus 89 ± 46 nmol peptide hydrolyzed/min/ml BAL fluid; p = 0.02). Serum NE/α1-AP complex also declined significantly in convalescent specimens (393 ± 58 versus 183 ± 24 μg/L; p = 0.0006) and approached levels near those of normal volunteer subjects (116 ± 10 μg/L), although convalescent levels were still significantly increased above levels for normal volunteers (p = 0.04). Intensive antibiotic therapy diminished free NE in BAL fluid, but a considerable amount of NE activity remained in lower respiratory tract secretions after such therapy. Our data show that although antibiotics are of some benefit in reducing specific markers of pulmonary inflammation in CF, other therapies such as the administration of antiproteases also may prove useful in treating patients with CF by modulating progressive, protease-mediated lung damage.

AB - 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 α1-antiprotease (α1-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 α1-AP to neutralize NE is impaired in CF, we compared NE activity in bronchoalveolar lavage (BAL) fluid and human neutrophil elastase/α1-antiprotease (NE/α1-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/α1-AP complex in BAL or peripheral blood and the degree of neutrophil influx, NE/α1-AP complex was disproportionately low in CF BAL compared with significantly elevated values in serum. These data suggest that in CF, α1-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. After 2 wk of intravenously administered antipseudomonal antibiotic therapy, free NE activity significantly diminished in BAL fluid (204 ± 102 versus 89 ± 46 nmol peptide hydrolyzed/min/ml BAL fluid; p = 0.02). Serum NE/α1-AP complex also declined significantly in convalescent specimens (393 ± 58 versus 183 ± 24 μg/L; p = 0.0006) and approached levels near those of normal volunteer subjects (116 ± 10 μg/L), although convalescent levels were still significantly increased above levels for normal volunteers (p = 0.04). Intensive antibiotic therapy diminished free NE in BAL fluid, but a considerable amount of NE activity remained in lower respiratory tract secretions after such therapy. Our data show that although antibiotics are of some benefit in reducing specific markers of pulmonary inflammation in CF, other therapies such as the administration of antiproteases also may prove useful in treating patients with CF by modulating progressive, protease-mediated lung damage.

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