Abstract

RATIONALE: Non-cystic fibrosis bronchiectasis (NCFB) 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: (a) measure mucus concentration and biophysical properties of bronchiectasis mucus; (b) identify the secreted mucins contained in bronchiectasis sputum; (c) relate mucus properties to airway epithelial mucin RNA/protein expression; and (d) explore relationships between mucus hyperconcentration and disease severity. METHODS: Sputum samples were collected from bronchiectasis subjects, with and without chronic erythromycin administration, and healthy controls. 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 polymorphisms were identified by qPCR. In a replication bronchiectasis cohort, spontaneously expectorated and hypertonic saline induced sputa were collected and mucus/mucin concentrations 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 bronchiectasis subjects, sputum percent solids correlated inversely with FEV1 and positively with bronchiectasis extent, as measured by high-resolution computerized tomography, and inflammatory mediators. No difference was detected in MUC5B rs35705950 SNP allele frequency between bronchiectasis and healthy individuals. Hypertonic saline inhalation acutely reduced NCFB mucus concentration by 25%. CONCLUSIONS: Hyper-concentrated airway mucus is characteristic of bronchiectasis subjects, likely contributes to disease pathophysiology, and may be a target for pharmacotherapy.

Authors	Ramsey, Kathryn A; Chen, Alice C H; Radicioni, Giorgia; Lourie, Rohan; Martin, Megan; Broomfield, Amy; Sheng, Yong H; Hasnain, Sumaira Z; Radford-Smith, Graham; Simms, Lisa A; Burr, Lucy; Thornton, David J; Bowler, Simon D; Livengood, Stephanie; Ceppe, Agathe; Knowles, Michael R; Donaldson, Scott H; Hill, David B; Ehre, Camille; Button, Brian; Alexis, Neil E; Kesimer, Mehmet; Boucher, Richard C; McGuckin, Michael A
Journal	AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Pages	661-670
Volume	201
Date	1/11/2019
Grant ID
Funding Body	Mater Adult Respiratory Research Trust Fund
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1164/rccm.201906-1219OC