scholarly journals Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis

2015 ◽  
Vol 46 (2) ◽  
pp. 384-394 ◽  
Author(s):  
Luke W. Garratt ◽  
Erika N. Sutanto ◽  
Kak-Ming Ling ◽  
Kevin Looi ◽  
Thomas Iosifidis ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Young Children ◽  
Neutrophil Elastase ◽  
Gelatin Zymography ◽  
Lavage Fluid ◽  
Causal Link ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Study Cohort ◽  
Elastase Activity ◽  
Structural Disease

Neutrophil elastase is the most significant predictor of bronchiectasis in early-life cystic fibrosis; however, the causal link between neutrophil elastase and airway damage is not well understood. Matrix metalloproteinases (MMPs) play a crucial role in extracellular matrix modelling and are activated by neutrophil elastase. The aim of this study was to assess if MMP activation positively correlates with neutrophil elastase activity, disease severity and bronchiectasis in young children with cystic fibrosis.Total MMP-1, MMP-2, MMP-7, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-1 levels were measured in bronchoalveolar lavage fluid collected from young children with cystic fibrosis during annual clinical assessment. Active/pro-enzyme ratio of MMP-9 was determined by gelatin zymography. Annual chest computed tomography imaging was scored for bronchiectasis.A higher MMP-9/TIMP-1 ratio was associated with free neutrophil elastase activity. In contrast, MMP-2/TIMP-2 ratio decreased and MMP-1 and MMP-7 were not detected in the majority of samples. Ratio of active/pro-enzyme MMP-9 was also higher in the presence of free neutrophil elastase activity, but not infection. Across the study cohort, both MMP-9/TIMP-1 and active MMP-9 were associated with progression of bronchiectasis.Both MMP-9/TIMP-1 and active MMP-9 increased with free neutrophil elastase and were associated with bronchiectasis, further demonstrating that free neutrophil elastase activity should be considered an important precursor to cystic fibrosis structural disease.

scholarly journals WS02.2 Role of soluble and membrane-associated neutrophil elastase activity in cystic fibrosis sputum

2017 ◽  
Vol 16 ◽  
pp. S3
Author(s):  
A.S. Dittrich ◽  
I. Kühbandner ◽  
S. Gehrig ◽  
V. Rickert-Zacharias ◽  
C.C. Taggart ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Neutrophil Elastase ◽  
Elastase Activity ◽  
Cystic Fibrosis Sputum

scholarly journals Changes in airway inflammation during pulmonary exacerbations in patients with cystic fibrosis and primary ciliary dyskinesia

2015 ◽  
Vol 47 (3) ◽  
pp. 829-836 ◽  
Author(s):  
Felix Ratjen ◽  
Valerie Waters ◽  
Michelle Klingel ◽  
Nancy McDonald ◽  
Sharon Dell ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Inflammatory Response ◽  
Neutrophil Elastase ◽  
Primary Ciliary Dyskinesia ◽  
Bacterial Pathogens ◽  
Pulmonary Exacerbation ◽  
Elastase Activity ◽  
Cell Counts ◽  
Pulmonary Exacerbations ◽  
Ciliary Dyskinesia

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.

Thioredoxin and dihydrolipoic acid inhibit elastase activity in cystic fibrosis sputum

2005 ◽  
Vol 289 (5) ◽  
pp. L875-L882 ◽  
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.

scholarly journals In Vitro Inhibition of Neutrophil Elastase Activity by Inhaled Anti-Pseudomonas Antibiotics Used in Cystic Fibrosis Patients

2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
Author(s):  
Andreas Hector ◽  
Matthias Kappler ◽  
Matthias Griese
Keyword(s):  
Cystic Fibrosis ◽  
Neutrophil Elastase ◽  
Direct Effects ◽  
Inhibitory Effects ◽  
Elastase Activity ◽  
Cystic Fibrosis Lung Disease ◽  
Inhaled Antibiotics ◽  
In Vitro Inhibition ◽  
High Concentrations

Background. Inhaled antibiotics are commonly used in the treatment of cystic fibrosis lung disease. A previous study suggested neutrophil elastase activation by colistin in vitro. Here, we investigated direct effects of the commonly used antibiotics colistin and tobramycin on neutrophil elastase activity.Methods. Neutrophil elastase was measured spectrophotometrically. The antibiotics colistin and tobramycin were added in different concentrations with or without the addition of albumin.Results. Generally, neutrophil elastase activity was lower in the absence of albumin compared to its presence. Both antibiotics, colistin and tobramycin, had inhibitory effects on neutrophil elastase activity except for high concentrations of colistin when albumin was absent.Conclusions. Our results suggest inhibitory effects of colistin and tobramycin in vitro. There was a clear dependency of neutrophil elastase measurements on the presence of albumin. Clinical studies are needed to investigate potential direct effects of inhaled antibiotics on neutrophil elastase activity in cystic fibrosis airways.

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