Impact of Airway Inflammation on the Efficacy of CFTR Modulators

Defective CFTR biogenesis and activity in cystic fibrosis airways leads to airway dehydration and impaired mucociliary clearance, resulting in chronic airway infection and inflammation. Most cystic fibrosis patients have at least one copy of the F508del CFTR mutation, which results in a protein reta...

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Autores principales:	Carla M. P. Ribeiro, Martina Gentzsch
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cystic fibrosis CFTR airway inflammation CFTR corrector CFTR potentiator F508del rescue Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/f9f44a2056ee478cb0717cd119c96584
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spelling	oai:doaj.org-article:f9f44a2056ee478cb0717cd119c965842021-11-25T17:13:23ZImpact of Airway Inflammation on the Efficacy of CFTR Modulators10.3390/cells101132602073-4409https://doaj.org/article/f9f44a2056ee478cb0717cd119c965842021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3260https://doaj.org/toc/2073-4409Defective CFTR biogenesis and activity in cystic fibrosis airways leads to airway dehydration and impaired mucociliary clearance, resulting in chronic airway infection and inflammation. Most cystic fibrosis patients have at least one copy of the F508del CFTR mutation, which results in a protein retained in the endoplasmic reticulum and degraded by the proteosomal pathway. CFTR modulators, e.g., correctors, promote the transfer of F508del to the apical membrane, while potentiators increase CFTR activity. Corrector and potentiator double therapies modestly improve lung function, whereas triple therapies with two correctors and one potentiator indicate improved outcomes. Enhanced F508del rescue by CFTR modulators is achieved by exposing F508del/F508del primary cultures of human bronchial epithelia to relevant inflammatory stimuli, i.e., supernatant from mucopurulent material or bronchoalveolar lavage fluid from human cystic fibrosis airways. Inflammation enhances the biochemical and functional rescue of F508del by double or triple CFTR modulator therapy and overcomes abrogation of CFTR correction by chronic VX-770 treatment in vitro. Furthermore, the impact of inflammation on clinical outcomes linked to CFTR rescue has been recently suggested. This review discusses these data and possible mechanisms for airway inflammation-enhanced F508del rescue. Expanding the understanding of how airway inflammation improves CFTR rescue may benefit cystic fibrosis patients.Carla M. P. RibeiroMartina GentzschMDPI AGarticlecystic fibrosisCFTRairway inflammationCFTR correctorCFTR potentiatorF508del rescueBiology (General)QH301-705.5ENCells, Vol 10, Iss 3260, p 3260 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cystic fibrosis CFTR airway inflammation CFTR corrector CFTR potentiator F508del rescue Biology (General) QH301-705.5
spellingShingle	cystic fibrosis CFTR airway inflammation CFTR corrector CFTR potentiator F508del rescue Biology (General) QH301-705.5 Carla M. P. Ribeiro Martina Gentzsch Impact of Airway Inflammation on the Efficacy of CFTR Modulators
description	Defective CFTR biogenesis and activity in cystic fibrosis airways leads to airway dehydration and impaired mucociliary clearance, resulting in chronic airway infection and inflammation. Most cystic fibrosis patients have at least one copy of the F508del CFTR mutation, which results in a protein retained in the endoplasmic reticulum and degraded by the proteosomal pathway. CFTR modulators, e.g., correctors, promote the transfer of F508del to the apical membrane, while potentiators increase CFTR activity. Corrector and potentiator double therapies modestly improve lung function, whereas triple therapies with two correctors and one potentiator indicate improved outcomes. Enhanced F508del rescue by CFTR modulators is achieved by exposing F508del/F508del primary cultures of human bronchial epithelia to relevant inflammatory stimuli, i.e., supernatant from mucopurulent material or bronchoalveolar lavage fluid from human cystic fibrosis airways. Inflammation enhances the biochemical and functional rescue of F508del by double or triple CFTR modulator therapy and overcomes abrogation of CFTR correction by chronic VX-770 treatment in vitro. Furthermore, the impact of inflammation on clinical outcomes linked to CFTR rescue has been recently suggested. This review discusses these data and possible mechanisms for airway inflammation-enhanced F508del rescue. Expanding the understanding of how airway inflammation improves CFTR rescue may benefit cystic fibrosis patients.
format	article
author	Carla M. P. Ribeiro Martina Gentzsch
author_facet	Carla M. P. Ribeiro Martina Gentzsch
author_sort	Carla M. P. Ribeiro
title	Impact of Airway Inflammation on the Efficacy of CFTR Modulators
title_short	Impact of Airway Inflammation on the Efficacy of CFTR Modulators
title_full	Impact of Airway Inflammation on the Efficacy of CFTR Modulators
title_fullStr	Impact of Airway Inflammation on the Efficacy of CFTR Modulators
title_full_unstemmed	Impact of Airway Inflammation on the Efficacy of CFTR Modulators
title_sort	impact of airway inflammation on the efficacy of cftr modulators
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/f9f44a2056ee478cb0717cd119c96584
work_keys_str_mv	AT carlampribeiro impactofairwayinflammationontheefficacyofcftrmodulators AT martinagentzsch impactofairwayinflammationontheefficacyofcftrmodulators
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Impact of Airway Inflammation on the Efficacy of CFTR Modulators

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