Mehmet Kesimer1, Amina A Ford1, Agathe Ceppe1, Giorgia Radicioni1, Rui Cao1, C William Davis1, Claire M Doerschuk1, Neil E Alexis1, Wayne H Anderson1, Ashley G Henderson1, R Graham Barr1, Eugene R Bleecker1, Stephanie A Christenson1, Christopher B Cooper1, MeiLan K Han1, Nadia N Hansel1, Annette T Hastie1, Eric A Hoffman1, Richard E Kanner1, Fernando Martinez1, Robert Paine1, Prescott G Woodruff1, Wanda K O'Neal1, Richard C Boucher1. 1. From the Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill (M.K., A.A.F., A.C., G.R., R.C., C.W.D., C.M.D., N.E.A., W.H.A., A.G.H., W.K.O., R.C.B.), and the Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem (E.R.B., A.T.H.) - both in North Carolina; the Department of Medicine, Columbia University Medical Center, and the Department of Epidemiology, Mailman School of Public Health at Columbia University (R.G.B.), and the Department of Medicine, Weill Cornell Medical College (F.M.), New York; the Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California San Francisco Medical Center, San Francisco (S.A.C., P.G.W.); the Department of Medicine and Physiology, David Geffen School of Medicine, University of California, Los Angeles (C.B.C.); the Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor (M.K.H.); the Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore (N.N.H.); the Department of Radiology, Division of Physiologic Imaging, University of Iowa Hospitals and Clinics, Iowa City (E.A.H.); and the Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Utah, Veterans Affairs Medical Center, Salt Lake City (R.E.K., R.P.).
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 chronic-bronchitis 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.).
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 chronic-bronchitis 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.).
Authors: Wayne H Anderson; Raymond D Coakley; Brian Button; Ashley G Henderson; Kirby L Zeman; Neil E Alexis; David B Peden; Eduardo R Lazarowski; C William Davis; Summer Bailey; Fred Fuller; Martha Almond; Bahjat Qaqish; Elena Bordonali; Michael Rubinstein; William D Bennett; Mehmet Kesimer; Richard C Boucher Journal: Am J Respir Crit Care Med Date: 2015-07-15 Impact factor: 21.405
Authors: B W M Willemse; N H T ten Hacken; B Rutgers; I G A T Lesman-Leegte; D S Postma; W Timens Journal: Eur Respir J Date: 2005-11 Impact factor: 16.671
Authors: Mehmet Kesimer; John Cullen; Rui Cao; Giorgia Radicioni; Kyle G Mathews; Gabriela Seiler; Jody L Gookin Journal: PLoS One Date: 2015-09-28 Impact factor: 3.240
Authors: Kathryn A Ramsey; Alice C H Chen; Giorgia Radicioni; Rohan Lourie; Megan Martin; Amy Broomfield; Yong H Sheng; Sumaira Z Hasnain; Graham Radford-Smith; Lisa A Simms; Lucy Burr; David J Thornton; Simon D Bowler; Stephanie Livengood; Agathe Ceppe; Michael R Knowles; Peadar G Noone; Scott H Donaldson; David B Hill; Camille Ehre; Brian Button; Neil E Alexis; Mehmet Kesimer; Richard C Boucher; Michael A McGuckin Journal: Am J Respir Crit Care Med Date: 2020-03-15 Impact factor: 21.405
Authors: Yun-Sung Lim; Yong Jun Choi; Bo Hae Kim; Hee-Bok Kim; Chang Gun Cho; Seok-Won Park; Joo Hyun Park Journal: In Vivo Date: 2020 May-Jun Impact factor: 2.155
Authors: Michael D Kim; Nathalie Baumlin; Makoto Yoshida; Deepika Polineni; Sebastian F Salathe; Joseph K David; Charles A Peloquin; Adam Wanner; John S Dennis; Juliette Sailland; Philip Whitney; Frank T Horrigan; Juan R Sabater; William M Abraham; Matthias Salathe Journal: Am J Respir Crit Care Med Date: 2020-02-01 Impact factor: 21.405
Authors: Richa Gupta; Giorgia Radicioni; Sabri Abdelwahab; Hong Dang; Jerome Carpenter; Michael Chua; Piotr A Mieczkowski; John T Sheridan; Scott H Randell; Mehmet Kesimer Journal: Am J Respir Cell Mol Biol Date: 2019-02 Impact factor: 6.914
Authors: Mehmet Kesimer; Benjamin M Smith; Agathe Ceppe; Amina A Ford; Wayne H Anderson; R Graham Barr; Wanda K O'Neal; Richard C Boucher Journal: Am J Respir Crit Care Med Date: 2018-12-01 Impact factor: 21.405