Deletion of airway cilia results in noninflammatory bronchiectasis and hyperreactive airways

Gilley, Sandra K.; Stenbit, Antine E.; Pasek, Raymond C.; Sas, Kelli M.; Steele, Stacy L.; Amria, May Y.; Bunni, Marlene A.; Estell, Kimberly P.; Schwiebert, Lisa M.; Flume, Patrick A.; Göõz, Monika; Haycraft, Courtney J.; Yoder, Bradley K.; Miller, Caroline; Pavlik, Jacqueline A.; Turner, G. Grey; Sisson, Joseph H.; Bell, P. Darwin

doi:10.1152/ajplung.00095.2013

Cited by 32 publications

(31 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This interpretation is consistent with findings in other mouse models that exhibit defective mucus transport but lack a mucus-adhesive component, e.g. , models of primary ciliary dyskinesia (PCD), which also exhibit a mild lower airway phenotype 3133 .…”

Section: Discussionsupporting

confidence: 91%

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

et al. 2017

View full text Add to dashboard Cite

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 to 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 airways 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: (1) mucus hyperconcentration dominates over MCC reduction alone to produce bronchitic airways pathology; (2) Muc5b is the dominant contributor to the Scnn1b-Tg phenotype; and (3) therapies that limit mucin secretion may reduce plugging, but complete Muc5b removal from airway surfaces may be detrimental.

show abstract

Section: Discussionsupporting

confidence: 91%

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

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Interestingly, a loss of airway cilia mobility was associated with an increase in airway reactivity in mice [35]. In the airways of individuals who have asthma, some areas of epithelial basement membrane seem to be denuded of ciliated cells [36].…”

Section: Discussionmentioning

confidence: 99%

Interaction between the DNAH9 gene and early smoke exposure in bronchial hyperresponsiveness

et al. 2016

View full text Add to dashboard Cite

A previous genome-wide linkage scan of bronchial hyperresponsiveness (BHR) in the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) families, performed in the presence of a gene×early-life environmental tobacco smoke (ETS) exposure interaction, showed the strongest interaction in the 17p11 region where linkage was detected only among unexposed siblings. Our goal was to conduct fine-scale mapping of 17p11 to identify single nucleotide polymorphisms (SNPs) interacting with ETS that influence BHR.Analyses were performed in 388 French EGEA asthmatic families, using a two-step strategy: 1) selection of SNPs displaying family-based association test (FBAT) association signals (p≤0.01) with BHR in unexposed siblings, and 2) a FBAT homogeneity test between exposed and unexposed siblings plus a robust log-linear interaction test.A single SNP reached the threshold (p≤3×10−3) for significant interaction with ETS using both interaction tests, after accounting for multiple testing. Results were replicated in 253 French-Canadian families, but not in 341 UK families, probably due in part to differences in phenotypic features between datasets.The SNP showing significant interaction with ETS belongs to DNAH9 (dynein, axonemal, heavy chain 9), a promising candidate gene involved in respiratory cilia mobility and associated with primary ciliary dyskinesia, a disease associated with abnormalities of pulmonary function.

show abstract

“…Gilley and colleagues reported that conditional deletion of motile cilia in the lung of the adult mouse results in slower cilia beating frequency and the development of bronchiectasis (23). They found that airway dilation in bronchiectasis was due to morphological changes of airway epithelial cells with cellular hyperplasia and proliferation of club cells, and led to loss of cilia and MCC impairment.…”

Section: Discussionmentioning

confidence: 99%

Aberrant epithelial remodeling with impairment of cilia architecture in non-cystic fibrosis bronchiectasis

Chen

Wang

et al. 2018

J. Thorac. Dis.

View full text Add to dashboard Cite

Background: Aberrant epithelial remodeling and/or abnormalities in mucociliary apparatus in airway epithelium contribute to infection and inflammation. It is uncertain if these changes occur in both large and small airways in non-cystic fibrosis bronchiectasis (non-CF bronchiectasis). In this study, we aim to investigate the histopathology and inflammatory profile in the epithelium of bronchi and bronchioles in bronchiectasis.Methods: Excised lung tissue sections from 52 patients with non-CF bronchiectasis were stained with specific cellular markers and analyzed by immunohistochemistry and immunofluorescence to assess the epithelial structures, including ciliated cells and goblet cells morphology. Inflammatory cell counts and ciliary proteins expression levels of centrosomal protein 110 (CP110) and dynein heavy chain 5, axonemal (DNAH5) were assessed.Results: Epithelial hyperplasia is found in both bronchi and bronchioles in all specimens, including hyperplasia and/or hypertrophy of goblet cells. The median cilia length is longer in hyperplastic epithelium [bronchi: 8.16 (7.03-9.14) μm, P<0.0001; bronchioles: 7.46 (6.41-8.48) μm, P<0.0001] as compared to nonhyperplastic epithelium (bronchi: 5.60 μm; bronchioles: 4.89 μm). Hyperplastic epithelium is associated with overexpression of CP110 and decreased intensity of DNAH5 expression in both bronchial and bronchiolar epithelium. Though infiltration of neutrophils is predominant (63.0% in bronchi and 76.7% in bronchioles), eosinophilic infiltration is also present in the mucosa of bronchi (30.8%) and bronchioles (54.8%).Conclusions: Aberrant epithelial remodeling with impaired mucociliary architecture is present in both large and small airways in patients with refractory non-CF bronchiectasis. Future studies should evaluate the interplay between these individual components in driving chronic inflammation and lung damage in patients.

show abstract

Deletion of airway cilia results in noninflammatory bronchiectasis and hyperreactive airways

Abstract: PD. Deletion of airway cilia results in noninflammatory bronchiectasis and hyperreactive airways.

Cited by 32 publications

References 35 publications

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

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

Interaction between the DNAH9 gene and early smoke exposure in bronchial hyperresponsiveness

Aberrant epithelial remodeling with impairment of cilia architecture in non-cystic fibrosis bronchiectasis

Contact Info

Product

Resources

About