Effects of Native and Oxidation-Resistant Secretory Leukoprotease Inhibitor on Cystic Fibrosis Sputum: Inhibition of Neutrophil Elastase Activity and of Sputum-Induced Secretion from Porcine Tracheal Submuc

Lung disease in patients with both primary ciliary dyskinesia (PCD) or cystic fibrosis (CF) is associated with impaired mucociliary clearance; however, clinical outcomes are typically worse in CF patients. We assessed whether CF and PCD patients differ in inflammatory response in the airways during pulmonary exacerbation.We first studied clinically stable PCD patients with a spectrum of bacterial pathogens to assess inflammatory response to different pathogens. Subsequently, PCD and CF patients with similar bacterial pathogens were studied at the time of a pulmonary exacerbation and after 21 days of antibiotics treatment. Qualitative and quantitative microbiology, cell counts, interleukin-8 concentrations, and neutrophil elastase activity were assessed in sputum samples obtained before and after treatment.In stable PCD patients, no significant differences were found in sputum inflammatory markers between individuals colonised with different bacterial pathogens. Pulmonary exacerbation severity assessed by a pulmonary exacerbation score and lung function decline from their previous baseline did not differ between CF and PCD patients. Bacterial density for Staphylococcus aureus and Haemophilus influenzae was higher in CF versus PCD (p<0.05), but absolute neutrophil counts were higher in PCD patients (p=0.02). While sputum elastase activity was similar in PCD and CF at the time of exacerbation, it decreased with antibiotic therapy in PCD (p<0.05) but not CF patients.PCD patients differ from those with CF in their responses to treatment of pulmonary exacerbations, with higher neutrophil elastase activity persisting in the CF airways at the end of treatment.

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Cytokine concentrations and neutrophil elastase activity in bronchoalveolar lavage and induced sputum from patients with cystic fibrosis, mild asthma and healthy volunteers

Journal of Cystic Fibrosis ◽

10.1016/s1569-1993(02)00098-x ◽

2002 ◽

Vol 1 (4) ◽

pp. 269-275 ◽

Cited By ~ 31

Author(s):

L.P.A McGarvey ◽

K Dunbar ◽

S.L Martin ◽

V Brown ◽

J MacMahon ◽

...

Keyword(s):

Cystic Fibrosis ◽

Bronchoalveolar Lavage ◽

Healthy Volunteers ◽

Neutrophil Elastase ◽

Induced Sputum ◽

Mild Asthma ◽

Elastase Activity

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145 A novel tool to study neutrophil elastase activity on neutrophils from cystic fibrosis airway secretions

Journal of Cystic Fibrosis ◽

10.1016/s1569-1993(12)60315-4 ◽

2012 ◽

Vol 11 ◽

pp. S93

Author(s):

S. Gehrig ◽

M.A. Mall ◽

C. Schultz

Keyword(s):

Cystic Fibrosis ◽

Neutrophil Elastase ◽

Elastase Activity ◽

Cystic Fibrosis Airway

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Thioredoxin and dihydrolipoic acid inhibit elastase activity in cystic fibrosis sputum

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00103.2005 ◽

2005 ◽

Vol 289 (5) ◽

pp. L875-L882 ◽

Cited By ~ 6

Author(s):

Rees L. Lee ◽

Raymond C. Rancourt ◽

Greg del Val ◽

Kami Pack ◽

Churee Pardee ◽

...

Keyword(s):

Cystic Fibrosis ◽

Neutrophil Elastase ◽

Disulfide Bonds ◽

Lung Damage ◽

Reduced Form ◽

Human Neutrophil Elastase ◽

Elastase Activity ◽

Dihydrolipoic Acid ◽

Dnase Treatment ◽

System 2

Excessive neutrophil elastase activity within airways of cystic fibrosis (CF) patients results in progressive lung damage. Disruption of disulfide bonds on elastase by reducing agents may modify its enzymatic activity. Three naturally occurring dithiol reducing systems were examined for their effects on elastase activity: 1) Escherichia coli thioredoxin (Trx) system, 2) recombinant human thioredoxin (rhTrx) system, and 3) dihydrolipoic acid (DHLA). The Trx systems consisted of Trx, Trx reductase, and NADPH. As shown by spectrophotometric assay of elastase activity, the two Trx systems and DHLA inhibited purified human neutrophil elastase as well as the elastolytic activity present in the soluble phase (sol) of CF sputum. Removal of any of the three Trx system constituents prevented inhibition. Compared with the monothiols N-acetylcysteine and reduced glutathione, the dithiols displayed greater elastase inhibition. To streamline Trx as an investigational tool, a stable reduced form of rhTrx was synthesized and used as a single component. Reduced rhTrx inhibited purified elastase and CF sputum sol elastase without NADPH or Trx reductase. Because Trx and DHLA have mucolytic effects, we investigated changes in elastase activity after mucolytic treatment. Unprocessed CF sputum was directly treated with reduced rhTrx, the Trx system, DHLA, or DNase. The Trx system and DHLA did not increase elastase activity, whereas reduced rhTrx treatment increased sol elastase activity by 60%. By contrast, the elastase activity after DNase treatment increased by 190%. The ability of Trx and DHLA to limit elastase activity combined with their mucolytic effects makes these compounds potential therapies for CF.

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