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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Bibliographic Details
Published in:Cells (Basel, Switzerland) Switzerland), 2021-11, Vol.10 (11), p.3260
Main Authors: Ribeiro, Carla M P, Gentzsch, Martina
Format: Article
Language:English
Subjects:
airway inflammation
Animals
Bacterial infections
Bronchus
CFTR
CFTR corrector
CFTR potentiator
Chronic infection
Clinical trials
Cystic fibrosis
Cystic Fibrosis - pathology
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
Cytokines
Dehydration
Endoplasmic reticulum
Evolution
F508del rescue
Humans
Infections
Inflammation
Inflammation - pathology
Lung - pathology
Lungs
Mutation
Patients
Pediatrics
Protein folding
Respiratory function
Respiratory tract
Respiratory tract diseases
Review
Translational Research, Biomedical
Treatment Outcome
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Summary: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.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells10113260