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

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.

Prevalence of and risk factors for presenting initial respiratory symptoms in patients undergoing surgery for lung cancer

“…Comorbidity of COPD was further proved to be an independent risk factor for presenting initial respiratory symptoms. To some extent, this can be explained by the hypothesis that tumors may be more easily to obstruct the otherwise narrowed airways with hyper-mucus secretion in patients with COPD 22 and thus cause initial respiratory symptoms early.…”

CARBOCISTEINE INHIBITS THE EXPRESSION OF Muc5b IN COPD MOUSE MODEL

“…1,3 Roy and colleagues showed that Muc5b, but not Muc5ac, was required for airway defense and that the decrease of Muc5b could hamper mucus clearance. 19 Additionally, publications have stated that the levels of MUC5B in BALF and sputum were increased in COPD patients, [32][33][34] while carbocisteine could balance fucosylated and sialylated sugar chains, 13 normalize the viscous property of mucus 12 and reduce MUC5AC expression. We speculated that the decrease of Muc5b might have played an important role in COPD pathogenesis and carbocisteine might reduce the expression of Muc5b in COPD mice model.…”

The Potential Role and Regulatory Mechanisms of MUC5AC in Chronic Obstructive Pulmonary Disease

“…Cysteine-rich secretory, or gelatinous secretory mucin gives mucus its characteristic viscoelasticity and this property is critical to clearance of xenobiotics by ciliated cells. MUC5AC and MUC5B are the most important and abundant mucins, comprising about 75% of mucins [ 4 , 37 ]. These mucins are abundantly expressed in normal and stressed states.…”