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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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/11/3260 |
| _version_ | 1827676990533009408 |
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| author | Carla M. P. Ribeiro Martina Gentzsch |
| author_facet | Carla M. P. Ribeiro Martina Gentzsch |
| author_sort | Carla M. P. Ribeiro |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T05:36:56Z |
| format | Article |
| id | doaj.art-f9f44a2056ee478cb0717cd119c96584 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T05:36:56Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-f9f44a2056ee478cb0717cd119c965842023-11-22T22:53:38ZengMDPI AGCells2073-44092021-11-011011326010.3390/cells10113260Impact of Airway Inflammation on the Efficacy of CFTR ModulatorsCarla M. P. Ribeiro0Martina Gentzsch1Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USAMarsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USADefective 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.https://www.mdpi.com/2073-4409/10/11/3260cystic fibrosisCFTRairway inflammationCFTR correctorCFTR potentiatorF508del rescue |
| spellingShingle | Carla M. P. Ribeiro Martina Gentzsch Impact of Airway Inflammation on the Efficacy of CFTR Modulators Cells cystic fibrosis CFTR airway inflammation CFTR corrector CFTR potentiator F508del rescue |
| title | 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_short | Impact of Airway Inflammation on the Efficacy of CFTR Modulators |
| title_sort | impact of airway inflammation on the efficacy of cftr modulators |
| topic | cystic fibrosis CFTR airway inflammation CFTR corrector CFTR potentiator F508del rescue |
| url | https://www.mdpi.com/2073-4409/10/11/3260 |
| work_keys_str_mv | AT carlampribeiro impactofairwayinflammationontheefficacyofcftrmodulators AT martinagentzsch impactofairwayinflammationontheefficacyofcftrmodulators |