Airway Mucin Concentration as a Marker of Chronic Bronchitis

Abstract

BACKGROUND Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitic and emphysematous components. In one biophysical model, the concentration of mucin on the airway surfaces is hypothesized to be a key variable that controls mucus transport in healthy persons versus cessation of transport in persons with muco-obstructive lung diseases. Under this model, it is postulated that a high mucin concentration produces the sputum and disease progression that are characteristic of chronic bronchitis. METHODS We characterized the COPD status of 917 participants from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) using questionnaires administered to participants, chest tomography, spirometry, and examination of induced sputum. Total mucin concentrations in sputum were measured with the use of size-exclusion chromatography and refractometry. In 148 of these participants, the respiratory secreted mucins MUC5AC and MUC5B were quantitated by means of mass spectrometry. Data from chronicbronchitis questionnaires and data on total mucin concentrations in sputum were also analyzed in an independent 94-participant cohort. RESULTS Mean (±SE) total mucin concentrations were higher in current or former smokers with severe COPD than in controls who had never smoked (3166±402 vs. 1515±152 μg per milliliter) and were higher in participants with two or more respiratory exacerbations per year than in those with zero exacerbations (4194±878 vs. 2458±113 μg per milliliter). The absolute concentrations of MUC5B and MUC5AC in current or former smokers with severe COPD were approximately 3 times as high and 10 times as high, respectively, as in controls who had never smoked. Receiver-operating-characteristic curve analysis of the association between total mucin concentration and a diagnosis of chronic bronchitis yielded areas under the curve of 0.72 (95% confidence interval [CI], 0.65 to 0.79) for the SPIROMICS cohort and 0.82 (95% CI, 0.73 to 0.92) for the independent cohort. CONCLUSIONS Airway mucin concentrations may quantitate a key component of the chronic bronchitis pathophysiologic cascade that produces sputum and mediates disease severity. Studies designed to explore total mucin concentrations in sputum as a diagnostic biomarker and therapeutic target for chronic bronchitis appear to be warranted. (Funded by the National Heart, Lung, and Blood Institute and others.)

Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets

“…Studies that demonstrate the eventual reoccurrence of bacterial colonization of ivacaftor-treated G551D-CFTR patients supports this notion of bacterial adaptation within the host despite CFTR functional restoration (10). Third, our findings support the notion that mucus accumulation, even in the absence of bacterial infection, is proinflammatory and that these processes can lead to significant structural remodeling in the CF lung (31,32). Notably, the proteomics inflammatory signature in BAL from CF ferrets with continuous bacterial eradication was strikingly similar to BAL from colonized human CF subjects (30).…”

“…This finding may be due to the fact that submucosal glands in the ferret are found throughout the cartilaginous airways, in contrast to mice, and could provide larger amounts of Muc5B and other inhibitors that prevent NE activation (27,29). On the whole, however, these studies also implicate mucus accumulation in the lung as proinflammatory (31,32). Furthermore, a recent study in chronically infected adult G551D-CFTR CF patients treated with ivacaftor (Kalydeco, VX770) demonstrated only transient (,1 yr) reductions in sputum bacterial loads, but sustained reductions in inflammatory factors (10).…”

Oxidative and endoplasmic reticulum stress in respiratory disease

“…However, if the increased production of mucin proteins is not resolved, mucus accumulation may contribute to the pathogenesis of human inflammatory airway disorders. Overproduction of airway mucus is a common problem in many airway diseases including bronchiectasis, CF and COPD where increased concentration of mucins in mucus is a key characteristic 36, 37…”

Mucins and their receptors in chronic lung disease

“…This results in repeated infections with mucus viscosity impairing the action of antimicrobial proteins secreted by the airway epithelial cell. These airways have elevated levels of NE, which correlates with disease severity and drives the development of bronchiectasis as NE‐induced mucus is more adherent …”