title: Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease.
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.
authors.affiliation: University of North Carolina Marsico Lung Institute/ Cystic Fibrosis Center, School of Medicine, The University of North Carolina at Chapel Hill, 125 Mason Farm Rd. 27599, Chapel Hill, NC, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Livraghi-Butrico
authors.affiliation: University of North Carolina Marsico Lung Institute/ Cystic Fibrosis Center, School of Medicine, The University of North Carolina at Chapel Hill, 125 Mason Farm Rd. 27599, Chapel Hill, NC, USA.
authors.forename: Barbara R
authors.initials: BR
authors.lastname: Grubb
authors.affiliation: University of North Carolina Marsico Lung Institute/ Cystic Fibrosis Center, School of Medicine, The University of North Carolina at Chapel Hill, 125 Mason Farm Rd. 27599, Chapel Hill, NC, USA.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Wilkinson
authors.affiliation: University of North Carolina Marsico Lung Institute/ Cystic Fibrosis Center, School of Medicine, The University of North Carolina at Chapel Hill, 125 Mason Farm Rd. 27599, Chapel Hill, NC, USA.
authors.forename: Allison S
authors.initials: AS
authors.lastname: Volmer
authors.affiliation: University of North Carolina Marsico Lung Institute/ Cystic Fibrosis Center, School of Medicine, The University of North Carolina at Chapel Hill, 125 Mason Farm Rd. 27599, Chapel Hill, NC, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Burns
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, 12700 E 19th Avenue, Mailstop 8611, Research Complex 2, Room 3121, Aurora, Colorado 80045, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Evans
authors.affiliation: University of North Carolina Marsico Lung Institute/ Cystic Fibrosis Center, School of Medicine, The University of North Carolina at Chapel Hill, 125 Mason Farm Rd. 27599, Chapel Hill, NC, USA.
authors.forename: Wanda K
authors.initials: WK
authors.lastname: O'Neal
authors.affiliation: University of North Carolina Marsico Lung Institute/ Cystic Fibrosis Center, School of Medicine, The University of North Carolina at Chapel Hill, 125 Mason Farm Rd. 27599, Chapel Hill, NC, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Boucher
mesh_terms: D000402:Airway Obstruction / Q000235:genetics; D000818:Animals; D001980:Bronchi / Q000473:pathology / Q000502:physiology*; D029481:Bronchitis, Chronic / Q000276:immunology*; D003550:Cystic Fibrosis / Q000276:immunology*; D053503:Epithelial Sodium Channels / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D007619:Kartagener Syndrome / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism*; D055257:Mucin-5B / Q000235:genetics / Q000378:metabolism*; D009079:Mucociliary Clearance / Q000235:genetics; D012907:Smoking / Q000009:adverse effects
chemical_list: D053503:Epithelial Sodium Channels; C524679:Muc5ac protein, mouse; C524579:Muc5b protein, mouse; D055271:Mucin 5AC; D055257:Mucin-5B; C507049:Scnn1b protein, mouse