Mucus concentration–dependent biophysical abnormalities unify submucosal gland and superficial airway dysfunction in cystic fibrosis-Reference-Cited by-同舟云学术

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

Published:2022-04 Issue:13 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Kato Takafumi¹²^ORCID,Radicioni Giorgia¹^ORCID,Papanikolas Micah J.³^ORCID,Stoychev Georgi V.¹^ORCID,Markovetz Matthew R.¹^ORCID,Aoki Kazuhiro⁴^ORCID,Porterfield Melody⁴^ORCID,Okuda Kenichi¹^ORCID,Barbosa Cardenas Selene M.¹^ORCID,Gilmore Rodney C.¹^ORCID,Morrison Cameron B.¹^ORCID,Ehre Camille¹⁵^ORCID,Burns Kimberlie A.¹,White Kristen K.⁶^ORCID,Brennan Tara A.¹,Goodell Henry P.¹,Thacker Holly¹,Loznev Henry T.¹,Forsberg Lawrence J.⁷^ORCID,Nagase Takahide²,Rubinstein Michael⁸^ORCID,Randell Scott H.¹^ORCID,Tiemeyer Michael⁴^ORCID,Hill David B.¹⁹^ORCID,Kesimer Mehmet¹^ORCID,O’Neal Wanda K.¹,Ballard Stephen T.¹⁰,Freeman Ronit³^ORCID,Button Brian¹^ORCID,Boucher Richard C.¹^ORCID

Affiliation:

1. Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

2. Department of Respiratory Medicine, University of Tokyo, Tokyo, Japan.

3. Department of Applied Physical Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

4. Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.

5. Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

6. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

7. Protein Expression and Purification Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

8. Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC, USA.

9. Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

10. Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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