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A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Pseudomonas aeruginosa Infection

People with cystic fibrosis (pwCF) suffer from chronic and recurring bacterial lung infections that begin very early in life and contribute to progressive lung failure. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes an ion channel important for mai...

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Autores principales: Cholon, Deborah M., Greenwald, Matthew A., Higgs, Matthew G., Quinney, Nancy L., Boyles, Susan E., Meinig, Suzanne L., Minges, John T., Chaubal, Ashlesha, Tarran, Robert, Ribeiro, Carla M. P., Wolfgang, Matthew C., Gentzsch, Martina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10670530/
https://www.ncbi.nlm.nih.gov/pubmed/37998353
http://dx.doi.org/10.3390/cells12222618
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author Cholon, Deborah M.
Greenwald, Matthew A.
Higgs, Matthew G.
Quinney, Nancy L.
Boyles, Susan E.
Meinig, Suzanne L.
Minges, John T.
Chaubal, Ashlesha
Tarran, Robert
Ribeiro, Carla M. P.
Wolfgang, Matthew C.
Gentzsch, Martina
author_facet Cholon, Deborah M.
Greenwald, Matthew A.
Higgs, Matthew G.
Quinney, Nancy L.
Boyles, Susan E.
Meinig, Suzanne L.
Minges, John T.
Chaubal, Ashlesha
Tarran, Robert
Ribeiro, Carla M. P.
Wolfgang, Matthew C.
Gentzsch, Martina
author_sort Cholon, Deborah M.
collection PubMed
description People with cystic fibrosis (pwCF) suffer from chronic and recurring bacterial lung infections that begin very early in life and contribute to progressive lung failure. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes an ion channel important for maintaining the proper hydration of pulmonary surfaces. When CFTR function is ablated or impaired, airways develop thickened, adherent mucus that contributes to a vicious cycle of infection and inflammation. Therapeutics for pwCF, called CFTR modulators, target the CFTR defect directly, restoring airway surface hydration and mucociliary clearance. However, even with CFTR modulator therapy, bacterial infections persist. To develop a relevant model of diseased airway epithelium, we established a primary human airway epithelium culture system with persistent Pseudomonas aeruginosa infection. We used this model to examine the effects of CFTR modulators on CFTR maturation, CFTR function, and bacterial persistence. We found that the presence of P. aeruginosa increased CFTR mRNA, protein, and function. We also found that CFTR modulators caused a decrease in P. aeruginosa burden. These results demonstrate the importance of including live bacteria to accurately model the CF lung, and that understanding the effects of infection on CFTR rescue by CFTR modulators is critical to evaluating and optimizing drug therapies for all pwCF.
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spelling pubmed-106705302023-11-13 A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Pseudomonas aeruginosa Infection Cholon, Deborah M. Greenwald, Matthew A. Higgs, Matthew G. Quinney, Nancy L. Boyles, Susan E. Meinig, Suzanne L. Minges, John T. Chaubal, Ashlesha Tarran, Robert Ribeiro, Carla M. P. Wolfgang, Matthew C. Gentzsch, Martina Cells Article People with cystic fibrosis (pwCF) suffer from chronic and recurring bacterial lung infections that begin very early in life and contribute to progressive lung failure. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes an ion channel important for maintaining the proper hydration of pulmonary surfaces. When CFTR function is ablated or impaired, airways develop thickened, adherent mucus that contributes to a vicious cycle of infection and inflammation. Therapeutics for pwCF, called CFTR modulators, target the CFTR defect directly, restoring airway surface hydration and mucociliary clearance. However, even with CFTR modulator therapy, bacterial infections persist. To develop a relevant model of diseased airway epithelium, we established a primary human airway epithelium culture system with persistent Pseudomonas aeruginosa infection. We used this model to examine the effects of CFTR modulators on CFTR maturation, CFTR function, and bacterial persistence. We found that the presence of P. aeruginosa increased CFTR mRNA, protein, and function. We also found that CFTR modulators caused a decrease in P. aeruginosa burden. These results demonstrate the importance of including live bacteria to accurately model the CF lung, and that understanding the effects of infection on CFTR rescue by CFTR modulators is critical to evaluating and optimizing drug therapies for all pwCF. MDPI 2023-11-13 /pmc/articles/PMC10670530/ /pubmed/37998353 http://dx.doi.org/10.3390/cells12222618 Text en © 2023 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
Cholon, Deborah M.
Greenwald, Matthew A.
Higgs, Matthew G.
Quinney, Nancy L.
Boyles, Susan E.
Meinig, Suzanne L.
Minges, John T.
Chaubal, Ashlesha
Tarran, Robert
Ribeiro, Carla M. P.
Wolfgang, Matthew C.
Gentzsch, Martina
A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Pseudomonas aeruginosa Infection
title A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Pseudomonas aeruginosa Infection
title_full A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Pseudomonas aeruginosa Infection
title_fullStr A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Pseudomonas aeruginosa Infection
title_full_unstemmed A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Pseudomonas aeruginosa Infection
title_short A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Pseudomonas aeruginosa Infection
title_sort novel co-culture model reveals enhanced cftr rescue in primary cystic fibrosis airway epithelial cultures with persistent pseudomonas aeruginosa infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10670530/
https://www.ncbi.nlm.nih.gov/pubmed/37998353
http://dx.doi.org/10.3390/cells12222618
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