Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction

BACKGROUND. The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. METHODS. In clinical studies, we developed and applied a bronchopulmonary segment–based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation. RESULTS. Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in ≥ 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%–80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. CONCLUSION. Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma. TRIAL REGISTRATION. Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915. FUNDING. NIH grants P01 HL107201, R01 HL080414, U10 HL109146, U10 HL109164, U10 HL109172, U10 HL109086, U10 HL109250, U10 HL109168, U10 HL109257, U10 HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428.

[1]  Ke Wang,et al.  Cough and Expectoration , 2019, Handbook of Clinical Diagnostics.

[2]  H. Simon,et al.  Eosinophilic bioactivities in severe asthma , 2016, The World Allergy Organization journal.

[3]  D. Erle,et al.  Epithelial tethering of MUC5AC-rich mucus impairs mucociliary transport in asthma. , 2016, The Journal of clinical investigation.

[4]  S. Hazen,et al.  Oxidation increases mucin polymer cross-links to stiffen airway mucus gels , 2015, Science Translational Medicine.

[5]  P. Woodruff,et al.  Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. , 2014, The Journal of allergy and clinical immunology.

[6]  E. Bleecker,et al.  International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma , 2013, European Respiratory Journal.

[7]  D. Denning,et al.  Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria , 2013, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[8]  E. Bleecker,et al.  Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. , 2013, The Journal of allergy and clinical immunology.

[9]  Douglas C Johnson,et al.  Airway mucus function and dysfunction. , 2011, The New England journal of medicine.

[10]  P. Burgel,et al.  Mucus hypersecretion in COPD: should we only rely on symptoms? , 2010, European Respiratory Review.

[11]  T. Leto,et al.  Characterization of hydrogen peroxide production by Duox in bronchial epithelial cells exposed to Pseudomonas aeruginosa , 2010, FEBS letters.

[12]  S. Muller,et al.  Ex vivo sputum analysis reveals impairment of protease-dependent mucus degradation by plasma proteins in acute asthma. , 2009, American journal of respiratory and critical care medicine.

[13]  M. McGuckin,et al.  Structure and function of the polymeric mucins in airways mucus. , 2008, Annual review of physiology.

[14]  W. Busse,et al.  Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation. , 2008, Journal of applied physiology.

[15]  R. Ravazzolo,et al.  Thiocyanate Transport in Resting and IL-4-Stimulated Human Bronchial Epithelial Cells: Role of Pendrin and Anion Channels1 , 2007, The Journal of Immunology.

[16]  David J Erle,et al.  IL-13 and epidermal growth factor receptor have critical but distinct roles in epithelial cell mucin production. , 2007, American journal of respiratory cell and molecular biology.

[17]  C. Porsbjerg,et al.  Chronic mucus hypersecretion: a marker of asthma in young adults? , 2005, Respiratory medicine.

[18]  M. Ménache,et al.  Fractal geometry of airway remodeling in human asthma. , 2005, American journal of respiratory and critical care medicine.

[19]  P. Barnes,et al.  Parameters associated with persistent airflow obstruction in chronic severe asthma , 2004, European Respiratory Journal.

[20]  L. Corbetta,et al.  Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. , 2003, American journal of respiratory and critical care medicine.

[21]  Glenn D Prestwich,et al.  Disulfide cross-linked hyaluronan hydrogels. , 2002, Biomacromolecules.

[22]  E. Israel,et al.  Safety and reproducibility of sputum induction in asthmatic subjects in a multicenter study. , 2001, American journal of respiratory and critical care medicine.

[23]  S. Hazen,et al.  Eosinophil Peroxidase Oxidation of Thiocyanate , 2001, The Journal of Biological Chemistry.

[24]  J. Fahy,et al.  Comparison of two methods of collecting induced sputum in asthmatic subjects. , 1996, The European respiratory journal.

[25]  A A Bankier,et al.  Bronchial wall thickness: appropriate window settings for thin-section CT and radiologic-anatomic correlation. , 1996, Radiology.

[26]  J. Vestbo,et al.  Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. , 1996, American journal of respiratory and critical care medicine.

[27]  L. Hansson,et al.  Neurophysiology of the cough reflex. , 1996, The European respiratory journal.

[28]  E. Chi,et al.  Eosinophil peroxidase-induced mast cell secretion , 1980, The Journal of experimental medicine.

[29]  Cough and expectoration. Paris, October 3-4, 1979. , 1980, European journal of respiratory diseases. Supplement.

[30]  B. Cardell.  [THE PATHOLOGY OF BRONCHIAL ASTHMA]. , 1963, Recenti progressi in medicina.

[31]  M. Dunnill.  THE PATHOLOGY OF ASTHMA, WITH SPECIAL REFERENCE TO CHANGES IN THE BRONCHIAL MUCOSA , 1960, Journal of clinical pathology.

[32]  C. Jackson.  COUGH: BRONCHOSCOPIC OBSERVATIONS ON THE COUGH REFLEX , 1922 .