Altered protease and antiprotease balance during a COPD exacerbation contributes to mucus obstruction.

Shashi Chillappagari,Jenni Preuss,Gaurav Sarode,Poornima Mahavadi,Claus Vogelmeier,Bruce K Rubin,Sebastian Licht,Andreas Guenther,Christian Müller,Markus O Henke,Lutz Nahrlich

doi:10.1186/s12931-015-0247-x

Abstract

BackgroundProteases 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.MethodsWe 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).ResultsUnexpectedly, 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).ConclusionThere 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.

Highlights

Proteases play a major role in bacterial entrapment [5], pathogen phagocytosis [16], mucin hypersecretion and mucociliary clearance [9]
We have shown that increased secretion of serine proteases in cystic fibrosis (CF) can degrade the gel-forming mucins during the time of transport from peripheral airways to central airways [9]
We investigated the role of proteases and anti-proteases on COPD mucin stability and degradation during the course of an infectious and inflammatory exacerbation of COPD

Summary

Introduction

Proteases play a major role in bacterial entrapment [5], pathogen phagocytosis [16], mucin hypersecretion and mucociliary clearance [9]. In COPD there is a deficiency and decreased activity of anti-proteases [21, 30], contributing to emphysema [1] and mucus hypersecretion [4]. This protease and anti-protease imbalance has been suggested to result from neutrophil infiltration in the lung [3, 28]. Proteases have been shown to degrade airway mucin proteins and to damage the epithelium impairing mucociliary clearance. We hypothesized that increased protease levels would lead to mucin degradation in acute COPD exacerbations

Methods

Results

Conclusion