Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease

A. Livraghi-Butrico, B. R. Grubb, K. J. Wilkinson, A. S. Volmer, K. A. Burns, C. M. Evans, W. K. O'Neal, R. C. Boucher

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Abstract

Airway diseases, including cigarette smoke-induced chronic bronchitis, cystic fibrosis, and primary ciliary dyskinesia are associated with decreased mucociliary clearance (MCC). However, it is not known whether a simple reduction in MCC or concentration-dependent mucus adhesion to airway surfaces dominates disease pathogenesis or whether decreasing the concentration of secreted mucins may be therapeutic. To address these questions, Scnn1b-Tg mice, which exhibit airway mucus dehydration/adhesion, were compared and crossed with Muc5b-and Muc5ac-deficient mice. Absence of Muc5b caused a 90% reduction in MCC, whereas Scnn1b-Tg mice exhibited an ∼50% reduction. However, the degree of MCC reduction did not correlate with bronchitic airway pathology, which was observed only in Scnn1b-Tg mice. Ablation of Muc5b significantly reduced the extent of mucus plugging in Scnn1b-Tg mice. However, complete absence of Muc5b in Scnn1b-Tg mice was associated with increased airway inflammation, suggesting that Muc5b is required to maintain immune homeostasis. Loss of Muc5ac had few phenotypic consequences in Scnn1b-Tg mice. These data suggest that: (i) mucus hyperconcentration dominates over MCC reduction alone to produce bronchitic airway pathology; (ii) Muc5b is the dominant contributor to the Scnn1b-Tg phenotype; and (iii) therapies that limit mucin secretion may reduce plugging, but complete Muc5b removal from airway surfaces may be detrimental.

LanguageEnglish (US)
Pages395-407
Number of pages13
JournalMucosal Immunology
Volume10
Issue number2
DOIs
StatePublished - Mar 1 2017

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Obstructive Lung Diseases
Mucins
Mucus
Mucociliary Clearance
Kartagener Syndrome
Pathology
Chronic Bronchitis
Dehydration
Cystic Fibrosis
Smoke
Tobacco Products
Homeostasis
Inflammation
Phenotype
Therapeutics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease. / Livraghi-Butrico, A.; Grubb, B. R.; Wilkinson, K. J.; Volmer, A. S.; Burns, K. A.; Evans, C. M.; O'Neal, W. K.; Boucher, R. C.

In: Mucosal Immunology, Vol. 10, No. 2, 01.03.2017, p. 395-407.

Research output: Contribution to journalArticle

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