Mucus concentration-dependent biophysical abnormalities unify submucosal gland and superficial airway dysfunction in cystic fibrosis

Cystic fibrosis (CF) is characterized by abnormal transepithelial ion transport. However, a description of CF lung disease pathophysiology unifying superficial epithelial and submucosal gland (SMG) dysfunctions has remained elusive. We hypothesized that biophysical abnormalities associated with CF m...

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Bibliographic Details
Published in:Science advances 2022-04, Vol.8 (13), p.eabm9718
Main Authors: Kato, Takafumi, Radicioni, Giorgia, Papanikolas, Micah J, Stoychev, Georgi V, Markovetz, Matthew R, Aoki, Kazuhiro, Porterfield, Melody, Okuda, Kenichi, Barbosa Cardenas, Selene M, Gilmore, Rodney C, Morrison, Cameron B, Ehre, Camille, Burns, Kimberlie A, White, Kristen K, Brennan, Tara A, Goodell, Henry P, Thacker, Holly, Loznev, Henry T, Forsberg, Lawrence J, Nagase, Takahide, Rubinstein, Michael, Randell, Scott H, Tiemeyer, Michael, Hill, David B, Kesimer, Mehmet, O'Neal, Wanda K, Ballard, Stephen T, Freeman, Ronit, Button, Brian, Boucher, Richard C
Format: Article
Language:English
Subjects:
Animals
Biomedicine and Life Sciences
Cystic Fibrosis - metabolism
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
Health and Medicine
Mucus - metabolism
Respiratory System - metabolism
SciAdv r-articles
Sputum - metabolism
Swine
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Summary:Cystic fibrosis (CF) is characterized by abnormal transepithelial ion transport. However, a description of CF lung disease pathophysiology unifying superficial epithelial and submucosal gland (SMG) dysfunctions has remained elusive. We hypothesized that biophysical abnormalities associated with CF mucus hyperconcentration provide a unifying mechanism. Studies of the anion secretion-inhibited pig airway model of CF revealed elevated SMG mucus concentrations, osmotic pressures, and SMG mucus accumulation. Human airway studies revealed hyperconcentrated CF SMG mucus with raised osmotic pressures and cohesive forces predicted to limit SMG mucus secretion/release. Using proline-rich protein 4 (PRR4) as a biomarker of SMG secretion, CF sputum proteomics analyses revealed markedly lower PRR4 levels compared to healthy and bronchiectasis controls, consistent with a failure of CF SMGs to secrete mucus onto airway surfaces. Raised mucus osmotic/cohesive forces, reflecting mucus hyperconcentration, provide a unifying mechanism that describes disease-initiating mucus accumulation on airway surfaces and in SMGs of the CF lung.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abm9718