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Modulator Combination Improves In Vitro the Microrheological Properties of the Airway Surface Liquid of Cystic Fibrosis Airway Epithelia
Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a plasma membrane protein expressed on the apical surface of secretory epithelia of the airways. In the airways, defective or absent function of the CFTR protein d...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9569604/ https://www.ncbi.nlm.nih.gov/pubmed/36232697 http://dx.doi.org/10.3390/ijms231911396 |
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author | Ludovico, Alessandra Moran, Oscar Baroni, Debora |
author_facet | Ludovico, Alessandra Moran, Oscar Baroni, Debora |
author_sort | Ludovico, Alessandra |
collection | PubMed |
description | Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a plasma membrane protein expressed on the apical surface of secretory epithelia of the airways. In the airways, defective or absent function of the CFTR protein determines abnormalities of chloride and bicarbonate secretion and, in general, of the transepithelial homeostasis that lead to alterations of airway surface liquid (ASL) composition and properties. The reduction of ASL volume impairs ciliary beating with the consequent accumulation of a sticky mucus. This situation prevents normal mucociliary clearance, favoring the survival and proliferation of bacteria and contributing to the genesis of the CF pulmonary disease. We explored the potential of some CFTR modulators, namely ivacaftor, tezacaftor, elexacaftor and their combination Kaftrio(TM), capable of partially recovering the basic defects of the CFTR protein, to ameliorate the transepithelial fluid transport and the viscoelastic properties of the mucus when used singly or in combination. Primary human bronchial epithelial cells obtained from CF and non-CF patients were differentiated into a mucociliated epithelia in order to assess the effects of correctors tezacaftor, elexacaftor and their combination with potentiator ivacaftor on the key properties of ASL, such as fluid reabsorption, viscosity, protein content and pH. The treatment of airway epithelia bearing the deletion of a phenylalanine at position 508 (F508del) in the CFTR gene with tezacaftor and elexacaftor significantly improved the pericilial fluid composition, reducing the fluid reabsorption, correcting the ASL pH and reducing the viscosity of the mucus. Kaftrio(TM) was more effective than single modulators in improving all the evaluated parameters, demonstrating once more that this combination recently approved for patients 6 years and older with cystic fibrosis who have at least one F508del mutation in the CFTR gene represents a valuable tool to defeat CF. |
format | Online Article Text |
id | pubmed-9569604 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-95696042022-10-17 Modulator Combination Improves In Vitro the Microrheological Properties of the Airway Surface Liquid of Cystic Fibrosis Airway Epithelia Ludovico, Alessandra Moran, Oscar Baroni, Debora Int J Mol Sci Article Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a plasma membrane protein expressed on the apical surface of secretory epithelia of the airways. In the airways, defective or absent function of the CFTR protein determines abnormalities of chloride and bicarbonate secretion and, in general, of the transepithelial homeostasis that lead to alterations of airway surface liquid (ASL) composition and properties. The reduction of ASL volume impairs ciliary beating with the consequent accumulation of a sticky mucus. This situation prevents normal mucociliary clearance, favoring the survival and proliferation of bacteria and contributing to the genesis of the CF pulmonary disease. We explored the potential of some CFTR modulators, namely ivacaftor, tezacaftor, elexacaftor and their combination Kaftrio(TM), capable of partially recovering the basic defects of the CFTR protein, to ameliorate the transepithelial fluid transport and the viscoelastic properties of the mucus when used singly or in combination. Primary human bronchial epithelial cells obtained from CF and non-CF patients were differentiated into a mucociliated epithelia in order to assess the effects of correctors tezacaftor, elexacaftor and their combination with potentiator ivacaftor on the key properties of ASL, such as fluid reabsorption, viscosity, protein content and pH. The treatment of airway epithelia bearing the deletion of a phenylalanine at position 508 (F508del) in the CFTR gene with tezacaftor and elexacaftor significantly improved the pericilial fluid composition, reducing the fluid reabsorption, correcting the ASL pH and reducing the viscosity of the mucus. Kaftrio(TM) was more effective than single modulators in improving all the evaluated parameters, demonstrating once more that this combination recently approved for patients 6 years and older with cystic fibrosis who have at least one F508del mutation in the CFTR gene represents a valuable tool to defeat CF. MDPI 2022-09-27 /pmc/articles/PMC9569604/ /pubmed/36232697 http://dx.doi.org/10.3390/ijms231911396 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ludovico, Alessandra Moran, Oscar Baroni, Debora Modulator Combination Improves In Vitro the Microrheological Properties of the Airway Surface Liquid of Cystic Fibrosis Airway Epithelia |
title | Modulator Combination Improves In Vitro the Microrheological Properties of the Airway Surface Liquid of Cystic Fibrosis Airway Epithelia |
title_full | Modulator Combination Improves In Vitro the Microrheological Properties of the Airway Surface Liquid of Cystic Fibrosis Airway Epithelia |
title_fullStr | Modulator Combination Improves In Vitro the Microrheological Properties of the Airway Surface Liquid of Cystic Fibrosis Airway Epithelia |
title_full_unstemmed | Modulator Combination Improves In Vitro the Microrheological Properties of the Airway Surface Liquid of Cystic Fibrosis Airway Epithelia |
title_short | Modulator Combination Improves In Vitro the Microrheological Properties of the Airway Surface Liquid of Cystic Fibrosis Airway Epithelia |
title_sort | modulator combination improves in vitro the microrheological properties of the airway surface liquid of cystic fibrosis airway epithelia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9569604/ https://www.ncbi.nlm.nih.gov/pubmed/36232697 http://dx.doi.org/10.3390/ijms231911396 |
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