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

Autor: Cholon DM; Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA., Greenwald MA; Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA., Higgs MG; Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA., Quinney NL; Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA., Boyles SE; Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA., Meinig SL; Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.; Pharmaceutical Product Development (PPD), Thermo Fisher Scientific, Morrisville, NC 27560, USA., Minges JT; Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA., Chaubal A; Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA., Tarran R; Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.; Division of Genetic, Department of Internal Medicine, Environmental and Inhalational Disease, University of Kansas Medical Center, Kansas City, KS 66160, USA., Ribeiro CMP; Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.; Division of Pulmonary Diseases, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.; Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA., Wolfgang MC; Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA., Gentzsch M; Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.; Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.; Division of Pediatric Pulmonology, Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Jazyk: angličtina
Zdroj: Cells [Cells] 2023 Nov 13; Vol. 12 (22). Date of Electronic Publication: 2023 Nov 13.
DOI: 10.3390/cells12222618
Abstrakt: 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.
Databáze: MEDLINE
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