Dataset Information

A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus.

ABSTRACT: Cystic fibrosis (CF) is characterized by increased mucus viscosity and delayed mucociliary clearance that contributes to progressive decline of lung function. Mucus in the respiratory and GI tract is excessively adhesive in the presence of airway dehydration and excess extracellular Ca2+ upon mucin release, promoting hyperviscous, densely packed mucins characteristic of CF. Therapies that target mucins directly through ionic interactions remain unexploited. Here we show that poly (acetyl, arginyl) glucosamine (PAAG), a polycationic biopolymer suitable for human use, interacts directly with mucins in a Ca2+-sensitive manner to reduce CF mucus viscoelasticity and improve its transport. Notably, PAAG induced a linear structure of purified MUC5B and altered its sedimentation profile and viscosity, indicative of proper mucin expansion. In vivo, PAAG nebulization improved mucociliary transport in CF rats with delayed mucus clearance, and cleared mucus plugging in CF ferrets. This study demonstrates the potential use of a synthetic glycopolymer PAAG as a molecular agent that could benefit patients with a broad array of mucus diseases.

SUBMITTER: Fernandez-Petty CM

PROVIDER: S-EPMC6538343 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus.

Fernandez-Petty Courtney M CM Hughes Gareth W GW Bowers Hannah L HL Watson John D JD Rosen Bradley H BH Townsend Stacy M SM Santos Carlo C Ridley Caroline E CE Chu Kengyeh K KK Birket Susan E. SE Li Yao Y Leung Hui Min HM Mazur Marina M Garcia Bryan A BA Evans T Idil Apak TIA Libby Emily Falk EF Hathorne Heather H Hanes Justin J Tearney Guillermo J GJ Clancy John P JP Engelhardt John F JF Swords William E WE Thornton David J DJ Wiesmann William P WP Baker Shenda M SM Rowe Steven M SM

JCI insight 20190418 8

Cystic fibrosis (CF) is characterized by increased mucus viscosity and delayed mucociliary clearance that contributes to progressive decline of lung function. Mucus in the respiratory and GI tract is excessively adhesive in the presence of airway dehydration and excess extracellular Ca2+ upon mucin release, promoting hyperviscous, densely packed mucins characteristic of CF. Therapies that target mucins directly through ionic interactions remain unexploited. Here we show that poly (acetyl, arginy ...[more]

PMID: 30996141

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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

A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus.

Publications

A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus.

Similar Datasets

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