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Hyperconcentrated Mucus Unifies Submucosal Gland and Superficial Airway Dysfunction in Cystic Fibrosis

Authors :
Kimberlie A. Burns
Brian Button
Richard C. Boucher
Micah J. Papanikolas
Stephen T. Ballard
Lawrence J. Forsberg
Giorgia Radicioni
Kenichi Okuda
Michael Rubinstein
Henry P. Goodell
David B. Hill
Henry T. Loznev
Takafumi Kato
Kristen K. White
Rodney C. Gilmore
Takahide Nagase
Mehmet Kesimer
Selene Margarita Barbosa Cardenas
Matthew R. Markovetz
Holly Thacker
Ronit Freeman
Scott H. Randell
Michael Tiemeyer
Cameron B. Morrison
Mindy Porterfield
Camille Ehre
Wanda K. O'Neal
Georgi Stoychev
Kazuhiro Aoki
Publication Year :
2021
Publisher :
Cold Spring Harbor Laboratory, 2021.

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 CF model 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. Utilizing proline-rich protein 4 (PRR4) as a biomarker of SMG secretion, proteomics analyses of CF sputum 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 within SMGs of the CF lung. One Sentence Summary Hyperconcentrated Mucus Unifies Submucosal Gland and Superficial Airway Dysfunction in Cystic Fibrosis

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........5f7ad9fe184ed86e58f8c8f68362e0a5