Pathological Mucus and Impaired Mucus Clearance in Cystic Fibrosis Patients Results from Increased Concentration, not altered pH
- David B. Hill1,2,
- Robert F. Long2,
- William J. Kissner2,
- Eyad Atieh2,
- Ian C. Garbarine2,
- Matthew R. Markovetz2,
- Nicholas C. Fontana2,
- Matthew Christy2,
- Mehdi Habibpour2,
- Robert Tarran2,3,
- M. Gregory Forest4,5,6,
- Richard C. Boucher2 and
- Brian Button2,6,7
- 1Department of Physics and Astronomy, The University of North Carolina at Chapel Hill
- 2Marsico Lung Institute / CF Center, The University of North Carolina at Chapel Hill
- 3Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill
- 4Department of Mathematics, The University of North Carolina at Chapel Hill
- 5Applied Physical Sciences, The University of North Carolina at Chapel Hill
- 6Department of Biomedical Engineering, The University of North Carolina at Chapel Hill
- 7Department of Biophysics and Biochemistry, The University of North Carolina at Chapel Hill
- David B. Hill. E-mail: dbhill{at}med.unc.edu
Abstract
Cystic fibrosis (CF) is a recessive genetic disease that is characterised by airway mucus plugging and reduced mucus clearance. There are currently alternative hypotheses that attempt to describe the abnormally viscous and elastic mucus that is a hallmark of CF airways disease, including: a) loss of cystic fibrosis transmembrane regulator (CFTR)-dependent airway surface volume (water) secretion, producing mucus hyper-concentration-dependent increased viscosity; and b) impaired bicarbonate secretion by CFTR, producing acidification of airway surfaces and increased mucus viscosity. A series of experiments were conducted to determine the contributions of mucus concentration versus pH to the rheological properties of airway mucus across length scales from the nanoscopic to macroscopic. Our results showed that, for length scales greater than the nanoscopic, i.e., those relevant to mucociliary clearance, the effect of mucus concentration dominated over the effect of airway acidification. Our data also showed that mucus hydration and chemical reduction of disulfide bonds that connect mucin monomers are more promising therapeutic approaches than alkalisation.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Hill reports grants from Cystic Fibrosis Foundation, grants from National Science Foundation, grants from National Institutes of Health, during the conduct of the study.
Conflict of interest: Dr. Long has nothing to disclose.
Conflict of interest: Dr. Kissner reports grants from NIH National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDKD) (Federal), grants from National Science Foundation (NSF) (Federal), grants from KNOW Bio, LLC (Business and Industry), grants from NIH National Heart, Lung, and Blood Institute (NHLBI) (Federal), grants from Cystic Fibrosis Foundation (Foundation), grants from Cystic Fibrosis Foundation Therapeutics (Foundation), during the conduct of the study.
Conflict of interest: Dr. Atieh has nothing to disclose.
Conflict of interest: Dr. Garbarine reports grants from Cystic Fibrosis Foundation, during the conduct of the study.
Conflict of interest: Dr. Markovetz has nothing to disclose.
Conflict of interest: Mr. Fontana has nothing to disclose.
Conflict of interest: Dr. Christy has nothing to disclose.
Conflict of interest: Dr. Tarran has nothing to disclose.
Conflict of interest: Dr. Boucher reports personal fees from Parion Sciences, outside the submitted work.
Conflict of interest: Dr. Button has nothing to disclose.
Conflict of interest: Dr. Habibpour has nothing to disclose.
Conflict of interest: Dr. Forest has nothing to disclose.
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