Epithelial tethering of MUC5AC-rich mucus impairs mucociliary transport in asthma

Bonser, Luke R.; Zlock, Lorna; Finkbeiner, Walter E.; Erle, David J.

doi:10.1172/jci84910

Cited by 165 publications

(195 citation statements)

References 25 publications

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“…In addition, we found that the ratio of gene expression of MUC5AC to MUC5B in sputum cells was significantly higher in the high mucus group than in the low and zero mucus groups and normalized following systemic corticosteroid treatment ( Figure 6E). The presteroid pattern of a high expression of MUC5AC relative to MUC5B in the high mucus group is typical of the activation effects of IL-13 on mucin expression by airway epithelial cells (17).…”

Section: Influence Of Airway Mucus Plugs On Treatment Responses To β mentioning

confidence: 84%

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

Dunican

Elicker²,

Gierada

et al. 2018

Journal of Clinical Investigation

392

324

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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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Section: Influence Of Airway Mucus Plugs On Treatment Responses To β mentioning

confidence: 84%

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

Dunican

Elicker²,

Gierada

et al. 2018

Journal of Clinical Investigation

392

324

View full text Add to dashboard Cite

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“…The swirls suggested increased mucus flow and enhanced MCC. Third, HS treatment exhibited gaps of low OCT signal just above the cell layer after 4.5 min (arrows), further suggesting rapid input of water (low signal), which would result in untethering of mucus from epithelial cells, further suggesting increased MCC, since tethered mucus has been shown to inhibit MCC 35 . Altogether, these results suggest HST may lead to sustained MCC.…”

Section: Resultsmentioning

confidence: 99%

Direct monitoring of pulmonary disease treatment biomarkers using plasmonic gold nanorods with diffusion-sensitive OCT

et al. 2017

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The solid concentration of pulmonary mucus (wt%) is critical to respiratory health. In patients with respiratory disease, such as Cystic Fibrosis (CF) and Chronic Obstructive Pulmonary Disorder (COPD), mucus hydration is impaired, resulting in high wt%. Mucus with high wt% is a hallmark of pulmonary disease that leads to obstructed airways, inflammation, and infection. Methods to measure mucus hydration in situ and in real-time are needed for drug development and personalized therapy. We employed plasmonic gold nanorod (GNR) biosensors that intermittently collide with macromolecules comprising the mucus mesh as they self-diffuse, such that GNR translational diffusion (DT) is sensitive to wt%. GNRs are attractive candidates for bioprobes due to their anisotropic optical scattering that makes them easily distinguishable from native tissue using polarization-sensitive OCT. Using principles of heterodyne dynamic light scattering, we developed diffusion-sensitive optical coherence tomography (DS-OCT) to spatially-resolve changing DT in real-time. DS-OCT enables, for the first time, direct monitoring of changes in nanoparticle diffusion rates that are sensitive to nanoporosity with spatial and temporal resolutions of 4.7 μm and 0.2 s. DS-OCT therefore enables us to measure spatially-resolved changes in mucus wt% over time. In this study, we demonstrate the applicability of DS-OCT on well-differentiated primary human bronchial epithelial cells during a clinical mucus-hydrating therapy, hypertonic saline treatment (HST), to reveal, for the first time, mucus mixing, cellular secretions, and mucus hydration on the micrometer scale that translate to long-term therapeutic effects.

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“…Potential etiologic pathways for high mucin concentrations, including cigarette smoking and asthma, were also explored. Because previous data suggested that overproduction of MUC5B is associated with COPD 13 and that overproduction of MUC5AC is associated with asthma, 14 absolute concentrations of MUC5AC and MUC5B were measured in a SPIROMICS subgroup and the relationships of each mucin to chronic bronchitis and asthma 15 were tested. Finally, the usefulness of total mucin concentrations in sputum as an objective biomarker for the diagnosis of chronic bronchitis was explored in SPIROMICS participants and participants in an independent cohort.…”

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confidence: 99%

Airway Mucin Concentration as a Marker of Chronic Bronchitis

et al. 2017

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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.)

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Epithelial tethering of MUC5AC-rich mucus impairs mucociliary transport in asthma

Cited by 165 publications

References 25 publications

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

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

Direct monitoring of pulmonary disease treatment biomarkers using plasmonic gold nanorods with diffusion-sensitive OCT

Airway Mucin Concentration as a Marker of Chronic Bronchitis

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