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The mucus bundles responsible for airway cleaning are retained in cystic fibrosis and by cholinergic stimulation.

ABSTRACT: The beneficial effect of anticholinergic therapy for chronic lung diseases such as chronic obstructive pulmonary disease (COPD) is well documented, although cholinergic stimulation paradoxically inhibits liquid absorption, increases ciliary beat frequency and increases airway surface liquid transport.Using pig tracheobronchial explants, we quantified basal mucus transport before as well as after incubation with the clinically used antimuscarinic compound ipratropium bromide (Atrovent) and stimulation with acetylcholine.As expected, surface liquid transport was increased by acetylcholine and carbachol. In contrast, the mucus bundles secreted from the submucosal glands normally transported on the cilia were stopped from moving by acetylcholine, an effect inhibited by ipratropium bromide. Interestingly, in pigs lacking a functional cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel, the mucus bundles were almost immobile. As in wild-type pigs, CF surface liquid transport increased after carbachol stimulation. The stagnant CF mucus bundles were trapped on the tracheal surface attached to the surface goblet cells. Pseudomonas aeruginosa bacteria were moved by the mucus bundles in wild-type but not CF pigs.Acetylcholine thus uncouples airway surface liquid transport from transport of the surface mucus bundles as the bundles are dynamically inhibited by acetylcholine and the CFTR channel, explaining initiation of CF and COPD, and opening novel therapeutic windows.

SUBMITTER: Ermund A

PROVIDER: S-EPMC6247115 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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The mucus bundles responsible for airway cleaning are retained in cystic fibrosis and by cholinergic stimulation.

Ermund Anna A Meiss Lauren N LN Dolan Brendan B Bähr Andrea A Klymiuk Nikolai N Hansson Gunnar C GC

The European respiratory journal 20180830 2

The beneficial effect of anticholinergic therapy for chronic lung diseases such as chronic obstructive pulmonary disease (COPD) is well documented, although cholinergic stimulation paradoxically inhibits liquid absorption, increases ciliary beat frequency and increases airway surface liquid transport.Using pig tracheobronchial explants, we quantified basal mucus transport before as well as after incubation with the clinically used antimuscarinic compound ipratropium bromide (Atrovent) and stimul ...[more]

PMID: 29853489

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Project description:Rationale: Non-cystic fibrosis bronchiectasis is characterized by airway mucus accumulation and sputum production, but the role of mucus concentration in the pathogenesis of these abnormalities has not been characterized.Objectives: This study was designed to: 1) measure mucus concentration and biophysical properties of bronchiectasis mucus; 2) identify the secreted mucins contained in bronchiectasis mucus; 3) relate mucus properties to airway epithelial mucin RNA/protein expression; and 4) explore relationships between mucus hyperconcentration and disease severity.Methods: Sputum samples were collected from subjects with bronchiectasis, with and without chronic erythromycin administration, and healthy control subjects. Sputum percent solid concentrations, total and individual mucin concentrations, osmotic pressures, rheological properties, and inflammatory mediators were measured. Intracellular mucins were measured in endobronchial biopsies by immunohistochemistry and gene expression. MUC5B (mucin 5B) polymorphisms were identified by quantitative PCR. In a replication bronchiectasis cohort, spontaneously expectorated and hypertonic saline-induced sputa were collected, and mucus/mucin concentrations were measured.Measurements and Main Results: Bronchiectasis sputum exhibited increased percent solids, total and individual (MUC5B and MUC5AC) mucin concentrations, osmotic pressure, and elastic and viscous moduli compared with healthy sputum. Within subjects with bronchiectasis, sputum percent solids correlated inversely with FEV1 and positively with bronchiectasis extent, as measured by high-resolution computed tomography, and inflammatory mediators. No difference was detected in MUC5B rs35705950 SNP allele frequency between bronchiectasis and healthy individuals. Hypertonic saline inhalation acutely reduced non-cystic fibrosis bronchiectasis mucus concentration by 5%.Conclusions: Hyperconcentrated airway mucus is characteristic of subjects with bronchiectasis, likely contributes to disease pathophysiology, and may be a target for pharmacotherapy.

Dataset Information

The mucus bundles responsible for airway cleaning are retained in cystic fibrosis and by cholinergic stimulation.

Publications

The mucus bundles responsible for airway cleaning are retained in cystic fibrosis and by cholinergic stimulation.

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