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

Abstract

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 H 2 O 2 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.

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“…The abnormally high levels of eosinophil peroxidase detected in the sputum of asthma patients may form an oxidative milieu. This would also bring the widely observed correlation between airway eosinophilia and airway obstruction into a causative relationship (102). Lastly, the MUC5AC of asthmatics tends to tether to the epithelium, which also complicates mucus forwarding (103).…”

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“…Although clear differences exist between airway and intestinal goblet cells, they share common features, such as low pH and high Ca 2+ content in their secretory granules, which allow for tight packaging of the mucus (4). Despite protective functions, mucus becomes a severe problem when hypersecreted upon mucous metaplasia during inflammatory lung diseases, such as asthma, chronic obstructive lung disease, and cystic fibrosis (CF) (5). Mucus hyperproduction causes airway obstruction, reduced mucociliary clearance, and chronic inflammation, the predominant problems in CF (3).…”

New biological treatments for asthma and skin allergies

“…Eosinophilia correlates to airway remodelling and mucus production. 11,[19][20][21][22] IL-13 plays an important role in airway bronchial hyper-reactivity, goblet-cell metaplasia and mucus production as well as in fibrosis 23 (Figure 1).…”