Airway mucin concentration as a marker of chronic bronchitis

Mehmet Kesimer, Amina A. Ford, Agathe Ceppe, Giorgia Radicioni, Rui Cao, C. William Davis, Claire M. Doerschuk, Neil E. Alexis, Wayne H. Anderson, Ashley G. Henderson, Graham R. Barr, Eugene R. Bleecker, Stephanie A. Christenson, Christopher B. Cooper, Mei Lan K. Han, Nadia Hansel, Annette T. Hastie, Eric A. Hoffman, Richard E. Kanner, Fernando MartinezRober Paine, Prescott G. Woodruff, Wanda K. O'Neal, Richard C. Boucher

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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.)

Original languageEnglish (US)
Pages (from-to)911-922
Number of pages12
JournalNew England Journal of Medicine
Volume377
Issue number10
DOIs
StatePublished - Sep 7 2017

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ASJC Scopus subject areas

  • Medicine(all)

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Kesimer, M., Ford, A. A., Ceppe, A., Radicioni, G., Cao, R., Davis, C. W., Doerschuk, C. M., Alexis, N. E., Anderson, W. H., Henderson, A. G., Barr, G. R., Bleecker, E. R., Christenson, S. A., Cooper, C. B., Han, M. L. K., Hansel, N., Hastie, A. T., Hoffman, E. A., Kanner, R. E., ... Boucher, R. C. (2017). Airway mucin concentration as a marker of chronic bronchitis. New England Journal of Medicine, 377(10), 911-922. https://doi.org/10.1056/NEJMoa1701632