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Mucus concentration-dependent biophysical abnormalities unify submucosal gland and superficial airway dysfunction in cystic fibrosis. Sci Adv 2022 Apr;8(13):eabm9718

Date

04/02/2022

Pubmed ID

35363522

Pubmed Central ID

PMC10938572

DOI

10.1126/sciadv.abm9718

Scopus ID

2-s2.0-85127523093 (requires institutional sign-in at Scopus site)   14 Citations

Abstract

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.

Author List

Kato T, Radicioni G, Papanikolas MJ, Stoychev GV, Markovetz MR, Aoki K, Porterfield M, Okuda K, Barbosa Cardenas SM, Gilmore RC, Morrison CB, Ehre C, Burns KA, White KK, Brennan TA, Goodell HP, Thacker H, Loznev HT, Forsberg LJ, Nagase T, Rubinstein M, Randell SH, Tiemeyer M, Hill DB, Kesimer M, O'Neal WK, Ballard ST, Freeman R, Button B, Boucher RC

Author

Kazuhiro Aoki PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cystic Fibrosis
Cystic Fibrosis Transmembrane Conductance Regulator
Mucus
Respiratory System
Sputum
Swine