Abnormalities in MUC5AC and MUC5B Protein in Airway Mucus in Asthma

Lachowicz-Scroggins, Marrah E.; Yuan, Shaopeng; Kerr, Sheena C.; Dunican, Eleanor M.; Yu, Michelle; Carrington, Stephen D.; Fahy, John V.

doi:10.1164/rccm.201603-0526le

Cited by 126 publications

(105 citation statements)

References 11 publications

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“…While these animal models establish the relationship between ICS and reduction in goblet cell volume, little is known about combination therapy or the effects on goblet cells in human asthma with the exclusion of a study performed with topical application of nasal corticosteroids in allergic rhinitis, which reduced goblet cell volume and numbers . We have also shown MUC5AC/5B gene and protein expression is up‐regulated in a subset of Th2 asthmatics, but in our previous work we did not correlate mucin expression to ICS or LABA use …”

Section: Introductionmentioning

confidence: 77%

Corticosteroid and long‐acting ß‐agonist therapy reduces epithelial goblet cell metaplasia

Lachowicz-Scroggins

Finkbeiner

Gordon

et al. 2017

Clin Experimental Allergy

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Corticosteroid treatment inhibits IL-13-induced GCM of the airways in asthma, possibly through its effects on SPDEF and FOXa2 regulation of mucin gene expression. These effects are modestly augmented by the addition of a long-acting ß-agonist. As we found evidence for drug treatment counteracting the effects of IL-13 on the epithelium, we conclude that further exploration into the mechanisms by which corticosteroids and long-acting β -adrenergic agonists confer protection against pathologic airway changes is warranted.

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Section: Introductionmentioning

confidence: 77%

Corticosteroid and long‐acting ß‐agonist therapy reduces epithelial goblet cell metaplasia

Lachowicz-Scroggins

Finkbeiner

Gordon

et al. 2017

Clin Experimental Allergy

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“…On the basis of reports that asthma is associated with mucin hypersecretion, 1,24 relationships between a diagnosis of current asthma and total mucin concentration were tested. Approximately 15% of the current or former smokers in the SPIROMICS cohort reported current asthma (Table S1C in the Supplementary Appendix), and those participants had higher total mucin concentrations than controls who had never smoked (Fig.…”

Section: Resultsmentioning

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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“…Mucociliary clearance, which depends on the cooperation between submucosal glands, goblet cells and ciliated cells, and normal chemical barrier function of the asthmatic epithelium are also compromised. There are profound changes in relative proportions and viscosity of mucins MUC5AC and MUC5B that in turn contribute to airway obstruction 33, 34 , and downregulation of lipoxins 35 . Perturbations in sphingolipid balance with increased levels of ceramides have also been reported in asthmatic airway epithelium 36 .…”

Section: Barrier Defects In Type 2 Diseasesmentioning

confidence: 99%

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

Schleimer

Berdnikovs

2017

Journal of Allergy and Clinical Immunology

134

122

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Epithelial barriers of the skin, gastrointestinal tract and airway serve common critical functions such as maintaining a physical barrier against environmental insults and allergens, as well as providing a tissue interface balancing the communication between the internal and external environments. We now understand that in allergic disease, regardless of tissue location, the homeostatic balance of the epithelial barrier is skewed towards loss of differentiation, reduced junctional integrity and impaired innate defense. Importantly, epithelial dysfunction characterized by these traits appears to pre-date atopy and development of allergic disease. Despite our growing appreciation of the centrality of barrier dysfunction in the initiation of allergic disease, many important questions remain to be answered regarding the mechanisms disrupting the normal barrier function. Although our external environment (proteases, allergens, injury) is classically thought of as a principal contributor to barrier disruption associated with allergic sensitization, there is a need to better understand contributions of the internal environment (hormones, diet, circadian clock). Systemic drivers of disease, such as alterations of the endocrine system, metabolism and aberrant control of developmental signaling, are emerging as new players in driving epithelial dysfunction and allergic predisposition at various barrier sites. Identifying such central mediators of epithelial dysfunction, using both systems biology tools and causality-driven laboratory experimentation, will be essential in building new strategic interventions to prevent or reverse the process of barrier loss in allergy.

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Abnormalities in MUC5AC and MUC5B Protein in Airway Mucus in Asthma

Cited by 126 publications

References 11 publications

Corticosteroid and long‐acting ß‐agonist therapy reduces epithelial goblet cell metaplasia

Corticosteroid and long‐acting ß‐agonist therapy reduces epithelial goblet cell metaplasia

Airway Mucin Concentration as a Marker of Chronic Bronchitis

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

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