Elsevier

Mucosal Immunology

Volume 10, Issue 2, March 2017, Pages 395-407
Mucosal Immunology

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

https://doi.org/10.1038/mi.2016.63Get rights and content
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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.

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Published online: 20 July 2016

Author contributions A.L.-B., W.K.O., and R.C.B. designed the study; K.J.W. and A.S.V. maintained mouse colonies, generated experimental animals, and collected body weight and survival data; A.L.B. and K.J.W. performed phenotyping experiments involving BAL analyses (differential cell counts, microbiology, etc.) and tissue harvest; K.A.B. provided histological specimens; A.L.-B. performed mucin agarose western blots, histopathological, immunohistochemistry/immunofluorescence, and morphometric analyses; B.R.G. performed and analyzed the data for the MCC assay; C.M.E., provided Muc5ac−/− and Muc5b−/− mice and reviewed the manuscript; A.L.-B. analyzed the rest of the data, and wrote the manuscript. B.R.G., W.K.O., and R.C.B. contributed to interpretation of the data and reviewed the manuscript.

SUPPLEMENTARY MATERIAL is linked to the online version of the paper

W K O'Neal and R C Boucher: These authors contributed equally to this work.

An erratum to this article is available online at https://doi.org/10.1038/mi.2017.29.