Treatment of cystic fibrosis airway cells with CFTR modulators reverses aberrant mucus properties
Journal
The European respiratory journal
ISSN: 1399-3003
Titre abrégé: Eur Respir J
Pays: England
ID NLM: 8803460
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
20
01
2021
accepted:
11
06
2021
pubmed:
27
6
2021
medline:
7
4
2022
entrez:
26
6
2021
Statut:
epublish
Résumé
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 ( 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. 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 HCO These results indicate that airway dehydration, not acidic pH and/or low [HCO
Identifiants
pubmed: 34172469
pii: 13993003.00185-2021
doi: 10.1183/13993003.00185-2021
pmc: PMC8859811
mid: NIHMS1778350
pii:
doi:
Substances chimiques
Bicarbonates
0
CFTR protein, human
0
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL108808
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK065988
Pays : United States
Informations de copyright
Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.
Déclaration de conflit d'intérêts
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.
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