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Altered protease and antiprotease balance during a COPD exacerbation contributes to mucus obstruction.
Respir. Res. 16:85 (2015)
Proteases have been shown to degrade airway mucin proteins and to damage the epithelium impairing mucociliary clearance. There are increased proteases in the COPD airway but changes in protease-antiprotease balance and mucin degradation have not been investigated during the course of a COPD exacerbation. We hypothesized that increased protease levels would lead to mucin degradation in acute COPD exacerbations. Methods: We measured neutrophil elastase (NE) and alpha 1 protease inhibitor (A1-PI) levels using immunoblotting, and conducted protease inhibitor studies, zymograms, elastin substrate assays and cigarette smoke condensate experiments to evaluate the stability of the gel-forming mucins, MUC5AC and MUC5B, before and 5-6 weeks after an acute pulmonary exacerbation of COPD (n=9 subjects). Results: Unexpectedly, mucin concentration and mucin stability were highest at the start of the exacerbation and restored to baseline after 6 weeks. Consistent with these data, immunoblots and zymograms confirmed decreased NE concentration and activity and increased A1-PI at the start of the exacerbation. After recovery there was an increase in NE activity and a decrease in A1-PI levels. In vitro, protease inhibitor studies demonstrated that serine proteases played a key role in mucin degradation. Mucin stability was further enhanced upon treating with cigarette smoke condensate (CSC). Conclusion: There appears to be rapid consumption of secreted proteases due to an increase in antiproteases, at the start of a COPD exacerbation. This leads to increased mucin gel stability which may be important in trapping and clearing infectious and inflammatory mediators, but this may also contribute acutely to mucus retention.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Alpha-1-protease Inhibitor ; Cigarette Smoke ; Copd ; Hypersecretion ; Mucin ; Neutrophil Elastase ; Proteases
ISSN (print) / ISBN
1465-9921
e-ISSN
1465-993X
Journal
Respiratory Research
Quellenangaben
Volume: 16,
Issue: 1,
Article Number: 85
Publisher
BioMed Central
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Lung Health and Immunity (LHI)