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Treatment of cystic fibrosis airway cells with CFTR modulators reverses aberrant mucus properties via hydration

Cameron B. Morrison, Kendall M. Shaffer, Kenza C. Araba, Matthew R. Markovetz, Jason A. Wykoff, Nancy L. Quinney, Shuyu Hao, Martial F. Delion, Alexis L. Flen, Lisa C. Morton, Jimmy Liao, David B. Hill, Mitchell L. Drumm, Wanda K. O'Neal, Mehmet Kesimer, Martina Gentzsch, Camille Ehre
European Respiratory Journal 2022 59: 2100185; DOI: 10.1183/13993003.00185-2021
Cameron B. Morrison
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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  • ORCID record for Cameron B. Morrison
Kendall M. Shaffer
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Kenza C. Araba
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Matthew R. Markovetz
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Jason A. Wykoff
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Nancy L. Quinney
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Shuyu Hao
2Dept of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Martial F. Delion
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Alexis L. Flen
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Lisa C. Morton
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Jimmy Liao
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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David B. Hill
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
3Dept of Physics and Astronomy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Mitchell L. Drumm
4Dept of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA
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Wanda K. O'Neal
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Mehmet Kesimer
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Martina Gentzsch
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2Dept of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
5Division of Pediatric Pulmonology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Camille Ehre
1Marsico Lung Institute/CF Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
5Division of Pediatric Pulmonology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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  • For correspondence: camille_ehre@med.unc.edu
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Abstract

Question Cystic fibrosis (CF) is characterised by the accumulation of viscous adherent mucus in the lungs. While several hypotheses invoke a direct relationship with cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction (i.e. acidic airway surface liquid (ASL) pH, low bicarbonate (HCO3−) concentration, airway dehydration), the dominant biochemical alteration of CF mucus remains unknown.

Materials/methods We characterised a novel cell line (CFTR-KO Calu3 cells) and the responses of human bronchial epithelial (HBE) cells from subjects with G551D or F508del mutations to ivacaftor and elexacaftor-tezacaftor-ivacaftor. A spectrum of assays such as short-circuit currents, quantitative PCR, ASL pH, Western blotting, light scattering/refractometry (size-exclusion chromatography with inline multi-angle light scattering), scanning electron microscopy, percentage solids and particle tracking were performed to determine the impact of CFTR function on mucus properties.

Results Loss of CFTR function in Calu3 cells resulted in ASL pH acidification and mucus hyperconcentration (dehydration). Modulation of CFTR in CF HBE cells did not affect ASL pH or mucin mRNA expression, but decreased mucus concentration, relaxed mucus network ultrastructure and improved mucus transport. In contrast with modulator-treated cells, a large fraction of airway mucins remained attached to naïve CF cells following short apical washes, as revealed by the use of reducing agents to remove residual mucus from the cell surfaces. Extended hydration, but not buffers alkalised with sodium hydroxide or HCO3−, normalised mucus recovery to modulator-treated cell levels.

Conclusion These results indicate that airway dehydration, not acidic pH and/or low [HCO3−], is responsible for abnormal mucus properties in CF airways and CFTR modulation predominantly restores normal mucin entanglement.

Abstract

CFTR rescue failed to normalise acidic pH, but reduced mucin concentration. Extended rehydration, not pH adjustment, facilitated mucus removal from cell surfaces, suggesting that mucus hydration is the dominant biochemical change in CF airways. https://bit.ly/3iKUzFd

Footnotes

  • Conflict of interest: C.B. Morrison has nothing to disclose.

  • Conflict of interest: K.M. Shaffer has nothing to disclose.

  • Conflict of interest: K.C. Araba has nothing to disclose.

  • Conflict of interest: M.R. Markovetz has nothing to disclose.

  • Conflict of interest: J.A. Wykoff has nothing to disclose.

  • Conflict of interest: N.L. Quinney has nothing to disclose.

  • Conflict of interest: S. Hao has nothing to disclose.

  • Conflict of interest: M.F. Delion has nothing to disclose.

  • Conflict of interest: A.L. Flen has nothing to disclose.

  • Conflict of interest: L.C. Morton has nothing to disclose.

  • Conflict of interest: J. Liao has nothing to disclose.

  • Conflict of interest: D.B. Hill has nothing to disclose.

  • Conflict of interest: M.L. Drumm has nothing to disclose.

  • Conflict of interest: W.K. O'Neal has nothing to disclose.

  • Conflict of interest: M. Kesimer has nothing to disclose.

  • Conflict of interest: M. Gentzsch has nothing to disclose.

  • Conflict of interest: C. Ehre has nothing to disclose.

  • Support statement: Work in part supported by grants from Vertex Pharmaceuticals (Ehre RIA Award), the Cystic Fibrosis Foundation (EHRE16XX1, EHRE20XX0, MARKOV18F0, HILL19G0 and HILL20Y2-OUT, BOUCHE19R0), the NIDDK (2 P30 DK 065988-16) and NHLBI (5 P01 HL 108808-08). Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received January 20, 2021.
  • Accepted June 11, 2021.
  • Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org
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Treatment of cystic fibrosis airway cells with CFTR modulators reverses aberrant mucus properties via hydration
Cameron B. Morrison, Kendall M. Shaffer, Kenza C. Araba, Matthew R. Markovetz, Jason A. Wykoff, Nancy L. Quinney, Shuyu Hao, Martial F. Delion, Alexis L. Flen, Lisa C. Morton, Jimmy Liao, David B. Hill, Mitchell L. Drumm, Wanda K. O'Neal, Mehmet Kesimer, Martina Gentzsch, Camille Ehre
European Respiratory Journal Feb 2022, 59 (2) 2100185; DOI: 10.1183/13993003.00185-2021

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Treatment of cystic fibrosis airway cells with CFTR modulators reverses aberrant mucus properties via hydration
Cameron B. Morrison, Kendall M. Shaffer, Kenza C. Araba, Matthew R. Markovetz, Jason A. Wykoff, Nancy L. Quinney, Shuyu Hao, Martial F. Delion, Alexis L. Flen, Lisa C. Morton, Jimmy Liao, David B. Hill, Mitchell L. Drumm, Wanda K. O'Neal, Mehmet Kesimer, Martina Gentzsch, Camille Ehre
European Respiratory Journal Feb 2022, 59 (2) 2100185; DOI: 10.1183/13993003.00185-2021
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