Normal nasal mucociliary clearance in CF children: evidence against a CFTR-related defect

McShane, D.; Davies, Jane C.; Wodehouse, Theresa; Bush, Andrew; Geddes, Duncan M.; Alton, Eric W.F.W.

doi:10.1183/09031936.04.00097503

Cited by 37 publications

(23 citation statements)

References 49 publications

(51 reference statements)

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“…In advanced cystic fibrosis (CF), airways show goblet cell hyperplasia and submucosal gland hypertrophy, and imaging of radiolabeled particles deposited in the lung indicates that MCT is reduced (1,3). The MCT reduction is greater as the severity of the disease increases, consistent with the finding that reduced MCT has not been detected in young people with CF (15,16).…”

supporting

confidence: 74%

Gel-forming mucins form distinct morphologic structures in airways

Ostedgaard

Moninger

McMenimen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

143

178

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Gel-forming mucins, the primary macromolecular components of airway mucus, facilitate airway clearance by mucociliary transport. In cystic fibrosis (CF) altered mucus properties impair mucociliary transport. Airways primarily secrete two closely related gel-forming mucins, MUC5B and MUC5AC. However, their morphologic structures and associations in airways that contain abundant submucosal glands and goblet cells are uncertain. Moreover, there is limited knowledge about mucins in airways not affected by inflammation, infection, or remodeling or in CF airways. Therefore, we examined airways freshly excised from newborn non-CF pigs and CF pigs before secondary manifestations develop. We found that porcine submucosal glands produce MUC5B, whereas goblet cells produce predominantly MUC5AC plus some MUC5B. We found that MUC5B emerged from submucosal gland ducts in the form of strands composed of multiple MUC5B filaments. In contrast, MUC5AC emerged from goblet cells as wispy threads and sometimes formed mucin sheets. In addition, MUC5AC often partially coated the MUC5B strands. Compared with non-CF, MUC5B more often filled CF submucosal gland ducts. MUC5AC sheets also accumulated in CF airways overlying MUC5B strands. These results reveal distinct morphology and interactions for MUC5B and MUC5AC and suggest that the two mucins make distinct contributions to mucociliary transport. Thus, they provide a framework for understanding abnormalities in disease.mucus | cystic fibrosis | lung | asthma | COPD

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supporting

confidence: 74%

Gel-forming mucins form distinct morphologic structures in airways

Ostedgaard

Moninger

McMenimen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

143

178

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“…In addition, radioisotope studies show that people with CF are able to clear labelled particles from their distal airways and studies have demonstrated conserved mucociliary transport in CF [37,38,39]. Experiments on the in vitro tissue culture model may give some explanation to this paradox [40].…”

Section: Airway Physiologymentioning

confidence: 99%

Cystic Fibrosis and Formes Frustes of CFTR-Related Disease

Southern

2007

Respiration

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Cystic fibrosis (CF) is the commonest genetic cause of bronchiectasis in the Caucasian population. Since identification of the putative gene in 1989, the molecular basis of the condition has become clearer with characterisation of the unique pathophysiology. The small airways are the primary site of lung disease, with an intense but localised inflammatory picture, dominated by neutrophils. The clinical heterogeneity is explained to some degree by the distinct molecular consequences of the many mutations that have been recognised to affect the CF transmembrane conductance regulator (CFTR) gene; however other genes appear to modify the phenotype as well as environmental exposure. It has become increasingly apparent that certain conditions may result from CFTR dysfunction without fulfilling diagnostic criteria for CF. In some cases this may result in single organ disease for which the term CF (or CFTR)-related disease has been advocated. Congenital bilateral absence of the vas deferens is the most clearly characterised of these. In other cases where a mild CF phenotype is apparent, atypical CF is probably a better term. It remains unclear whether carrier status predisposes to certain conditions such as chronic rhinosinusitis or pancreatitis.

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“…Studies have shown that altered biophysical properties of mucus, and possibly MCC dysfunction itself, are secondary to infection in both CF and PCD lung disease (McShane et al, 2004;Grubb et al, 2004;Bush et al, 2006). Viscoelasticity has recently been shown to be an important factor in the formation of bacterial colonies (Matsui et al, 2006).…”

Section: Airway Surface Liquid Rheologymentioning

confidence: 99%

Modelling mucociliary clearance

Smith

Gaffney

Blake

2008

Respiratory Physiology & Neurobiology

157

142

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a b s t r a c tMathematical modelling of the fluid mechanics of mucociliary clearance (MCC) is reviewed and future challenges for researchers are discussed. The morphology of the bronchial and tracheal airway surface liquid (ASL) and ciliated epithelium are briefly introduced. The cilia beat cycle, beat frequency and metachronal coordination are described, along with the rheology of the mucous layer. Theoretical modelling of MCC from the late 1960s onwards is reviewed, and distinctions between 'phenomenological', 'slender body theory' and recent 'fluid-structure interaction' models are explained.The ASL consists of two layers, an overlying mucous layer and underlying watery periciliary layer (PCL) which bathes the cilia. Previous models have predicted very little transport of fluid in the PCL compared with the mucous layer. Fluorescent tracer transport experiments on human airway cultures conducted by Matsui et al. [Matsui, H., Randell, S.H., Peretti, S.W., Davis, C.W., Boucher, R.C., 1998. Coordinated clearance of periciliary liquid and mucus from airway surfaces. J. Clin. Invest. 102 (6), 1125-1131] apparently showed equal transport in both the PCL and mucous layer. Recent attempts to resolve this discrepancy by the present authors are reviewed, along with associated modelling findings. These findings have suggested new insights into the interaction of cilia with mucus due to pressure gradients associated with the flat PCL/mucus interface. This phenomenon complements previously known mechanisms for ciliary propulsion. Modelling results are related to clinical findings, in particular the increased MCC observed in patients with pseudohypoaldosteronism. Recent important advances by several groups in modelling the fluid-structure interaction by which the cilia movement and fluid transport emerge from specification of internal mechanics, viscous and elastic forces are reviewed. Finally, we discuss the limitations of existing work, and the challenges for the next generation of models, which may provide further insight into this complex and vital system.

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Normal nasal mucociliary clearance in CF children: evidence against a CFTR-related defect

Cited by 37 publications

References 49 publications

Gel-forming mucins form distinct morphologic structures in airways

Gel-forming mucins form distinct morphologic structures in airways

Cystic Fibrosis and Formes Frustes of CFTR-Related Disease

Modelling mucociliary clearance

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