{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:18:18Z","timestamp":1790824698840,"version":"4.1.0"},"reference-count":93,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T00:00:00Z","timestamp":1699833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cystic Fibrosis Foundation (CFF)","award":["CHOLON1610"],"award-info":[{"award-number":["CHOLON1610"]}]},{"name":"Cystic Fibrosis Foundation (CFF)","award":["WOLFGA19G0"],"award-info":[{"award-number":["WOLFGA19G0"]}]},{"name":"Cystic Fibrosis Foundation (CFF)","award":["RDP BOUCHE19R0"],"award-info":[{"award-number":["RDP BOUCHE19R0"]}]},{"name":"Cystic Fibrosis Foundation (CFF)","award":["P30DK065988"],"award-info":[{"award-number":["P30DK065988"]}]},{"name":"Cystic Fibrosis Foundation (CFF)","award":["APP 1183640"],"award-info":[{"award-number":["APP 1183640"]}]},{"name":"FFCF","award":["CHOLON1610"],"award-info":[{"award-number":["CHOLON1610"]}]},{"name":"FFCF","award":["WOLFGA19G0"],"award-info":[{"award-number":["WOLFGA19G0"]}]},{"name":"FFCF","award":["RDP BOUCHE19R0"],"award-info":[{"award-number":["RDP BOUCHE19R0"]}]},{"name":"FFCF","award":["P30DK065988"],"award-info":[{"award-number":["P30DK065988"]}]},{"name":"FFCF","award":["APP 1183640"],"award-info":[{"award-number":["APP 1183640"]}]},{"name":"NIH","award":["CHOLON1610"],"award-info":[{"award-number":["CHOLON1610"]}]},{"name":"NIH","award":["WOLFGA19G0"],"award-info":[{"award-number":["WOLFGA19G0"]}]},{"name":"NIH","award":["RDP BOUCHE19R0"],"award-info":[{"award-number":["RDP BOUCHE19R0"]}]},{"name":"NIH","award":["P30DK065988"],"award-info":[{"award-number":["P30DK065988"]}]},{"name":"NIH","award":["APP 1183640"],"award-info":[{"award-number":["APP 1183640"]}]},{"name":"National Health and Medical Research Council of Australia (NHMRC)","award":["CHOLON1610"],"award-info":[{"award-number":["CHOLON1610"]}]},{"name":"National Health and Medical Research Council of Australia (NHMRC)","award":["WOLFGA19G0"],"award-info":[{"award-number":["WOLFGA19G0"]}]},{"name":"National Health and Medical Research Council of Australia (NHMRC)","award":["RDP BOUCHE19R0"],"award-info":[{"award-number":["RDP BOUCHE19R0"]}]},{"name":"National Health and Medical Research Council of Australia (NHMRC)","award":["P30DK065988"],"award-info":[{"award-number":["P30DK065988"]}]},{"name":"National Health and Medical Research Council of Australia (NHMRC)","award":["APP 1183640"],"award-info":[{"award-number":["APP 1183640"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cells12222618","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T08:35:52Z","timestamp":1699864552000},"page":"2618","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Novel Co-Culture Model Reveals Enhanced CFTR Rescue in Primary Cystic Fibrosis Airway Epithelial Cultures with Persistent Pseudomonas aeruginosa Infection"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9396-0005","authenticated-orcid":false,"given":"Deborah M.","family":"Cholon","sequence":"first","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4765-2738","authenticated-orcid":false,"given":"Matthew A.","family":"Greenwald","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"},{"name":"Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5460-4980","authenticated-orcid":false,"given":"Matthew G.","family":"Higgs","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"},{"name":"Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy L.","family":"Quinney","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan E.","family":"Boyles","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne L.","family":"Meinig","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"},{"name":"Pharmaceutical Product Development (PPD), Thermo Fisher Scientific, Morrisville, NC 27560, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John T.","family":"Minges","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashlesha","family":"Chaubal","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8598-2642","authenticated-orcid":false,"given":"Robert","family":"Tarran","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"},{"name":"Division of Genetic, Department of Internal Medicine, Environmental and Inhalational Disease, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5247-7060","authenticated-orcid":false,"given":"Carla M. P.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"},{"name":"Division of Pulmonary Diseases, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"},{"name":"Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4534-6470","authenticated-orcid":false,"given":"Matthew C.","family":"Wolfgang","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"},{"name":"Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9435-0321","authenticated-orcid":false,"given":"Martina","family":"Gentzsch","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"},{"name":"Department of Cell Biology and Physiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"},{"name":"Division of Pediatric Pulmonology, Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1146\/annurev.med.58.071905.105316","article-title":"Airway surface dehydration in cystic fibrosis: Pathogenesis and therapy","volume":"58","author":"Boucher","year":"2007","journal-title":"Annu. Rev. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1465-9921-4-8","article-title":"State of the art: Why do the lungs of patients with cystic fibrosis become infected and why can\u2019t they clear the infection?","volume":"4","author":"Chmiel","year":"2003","journal-title":"Respir. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7770","DOI":"10.1128\/JVI.00346-10","article-title":"Respiratory syncytial virus engineered to express the cystic fibrosis transmembrane conductance regulator corrects the bioelectric phenotype of human cystic fibrosis airway epithelium in vitro","volume":"84","author":"Kwilas","year":"2010","journal-title":"J. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"eaav3488","DOI":"10.1126\/scitranslmed.aav3488","article-title":"Mucus accumulation in the lungs precedes structural changes and infection in children with cystic fibrosis","volume":"11","author":"Esther","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.pcl.2016.04.003","article-title":"Cystic Fibrosis: Microbiology and Host Response","volume":"63","author":"Zemanick","year":"2016","journal-title":"Pediatr. Clin. N. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1128\/CMR.15.2.194-222.2002","article-title":"Lung infections associated with cystic fibrosis","volume":"15","author":"Lyczak","year":"2002","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1001\/jama.293.5.581","article-title":"Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis","volume":"293","author":"Li","year":"2005","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1093\/cid\/ciu385","article-title":"Pseudomonas aeruginosa phenotypes associated with eradication failure in children with cystic fibrosis","volume":"59","author":"Ramsey","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1056\/NEJMoa1105185","article-title":"A CFTR potentiator in patients with cystic fibrosis and the G551D mutation","volume":"365","author":"Ramsey","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1164\/rccm.201301-0153OC","article-title":"Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation","volume":"187","author":"Davies","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1056\/NEJMoa1409547","article-title":"Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR","volume":"373","author":"Wainwright","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1056\/NEJMoa1709846","article-title":"Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del","volume":"377","author":"Munck","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1056\/NEJMoa1709847","article-title":"Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis","volume":"377","author":"Rowe","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"246ra296","DOI":"10.1126\/scitranslmed.3008680","article-title":"Potentiator ivacaftor abrogates pharmacological correction of DeltaF508 CFTR in cystic fibrosis","volume":"6","author":"Cholon","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"246ra297","DOI":"10.1126\/scitranslmed.3008889","article-title":"Some gating potentiators, including VX-770, diminish DeltaF508-CFTR functional expression","volume":"6","author":"Veit","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1016\/S0140-6736(19)32597-8","article-title":"Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: A double-blind, randomised, phase 3 trial","volume":"394","author":"Heijerman","year":"2019","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1056\/NEJMoa1908639","article-title":"Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele","volume":"381","author":"Middleton","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1164\/rccm.202102-0509OC","article-title":"A Phase 3 Open-Label Study of Elexacaftor\/Tezacaftor\/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One F508del Allele","volume":"203","author":"Zemanick","year":"2021","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1164\/rccm.201910-1943SO","article-title":"Cystic Fibrosis: Emergence of Highly Effective Targeted Therapeutics and Potential Clinical Implications","volume":"201","author":"Mall","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"18825","DOI":"10.1073\/pnas.0904709106","article-title":"Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770","volume":"106","author":"Hadida","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1164\/rccm.201507-1271LE","article-title":"Intestinal Current Measurements Detect Activation of Mutant CFTR in Patients with Cystic Fibrosis with the G551D Mutation Treated with Ivacaftor","volume":"192","author":"Graeber","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1056\/NEJMoa0909825","article-title":"Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation","volume":"363","author":"Accurso","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1126\/science.2472006","article-title":"Regulation of chloride channels by protein kinase C in normal and cystic fibrosis airway epithelia","volume":"244","author":"Li","year":"1989","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e122695","DOI":"10.1172\/jci.insight.122695","article-title":"Effect of ivacaftor on mucociliary clearance and clinical outcomes in cystic fibrosis patients with G551D-CFTR","volume":"3","author":"Donaldson","year":"2018","journal-title":"JCI Insight"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1164\/rccm.201404-0703OC","article-title":"Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis","volume":"190","author":"Rowe","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1159\/000365999","article-title":"Improvement in bronchiectasis on CT imaging in a pediatric patient with cystic fibrosis on ivacaftor therapy","volume":"88","author":"Hayes","year":"2014","journal-title":"Respiration"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1164\/rccm.201403-0595IM","article-title":"Improvement of sinus disease in cystic fibrosis with ivacaftor therapy","volume":"190","author":"Hayes","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jcf.2014.06.011","article-title":"Computed tomography correlates with improvement with ivacaftor in cystic fibrosis patients with G551D mutation","volume":"14","author":"Sheikh","year":"2015","journal-title":"J. Cyst. Fibros."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s00408-014-9629-y","article-title":"CT imaging of pediatric patients with cystic fibrosis on ivacaftor therapy","volume":"192","author":"Hayes","year":"2014","journal-title":"Lung"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1164\/rccm.201308-1433IM","article-title":"Ivacaftor imaging response in cystic fibrosis","volume":"189","author":"Hoare","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/alr.21440","article-title":"Medical reversal of chronic sinusitis in a cystic fibrosis patient with ivacaftor","volume":"5","author":"Chang","year":"2015","journal-title":"Int. Forum Allergy Rhinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/coa.12310","article-title":"Ivacaftor improves appearance of sinus disease on computerised tomography in cystic fibrosis patients with G551D mutation","volume":"40","author":"Sheikh","year":"2015","journal-title":"Clin. Otolaryngol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e81","DOI":"10.1038\/ctg.2017.10","article-title":"Impact of CFTR Modulation on Intestinal pH, Motility, and Clinical Outcomes in Patients With Cystic Fibrosis and the G551D Mutation","volume":"8","author":"Gelfond","year":"2017","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1111\/pedi.12026","article-title":"Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: A small pilot study","volume":"14","author":"Bellin","year":"2013","journal-title":"Pediatr. Diabetes"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e25","DOI":"10.1016\/j.jcf.2015.10.012","article-title":"CFTR potentiator therapy ameliorates impaired insulin secretion in CF patients with a gating mutation","volume":"15","author":"Tsabari","year":"2016","journal-title":"J. Cyst. Fibros."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1164\/rccm.201405-0882LE","article-title":"Resolution of cystic fibrosis-related diabetes with ivacaftor therapy","volume":"190","author":"Hayes","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1056\/NEJMoa1807120","article-title":"VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles","volume":"379","author":"Keating","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1164\/rccm.201609-1954OC","article-title":"Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections","volume":"195","author":"Hisert","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1093\/cid\/ciu944","article-title":"Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor","volume":"60","author":"Heltshe","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e167957","DOI":"10.1172\/JCI167957","article-title":"Pharmacologic improvement of CFTR function rapidly decreases sputum pathogen density, but lung infections generally persist","volume":"133","author":"Nichols","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2202153","DOI":"10.1183\/13993003.02153-2022","article-title":"Longitudinal Effects of Elexacaftor\/Tezacaftor\/Ivacaftor on Sputum Viscoelastic Properties, Airway Infection and Inflammation in Patients with Cystic Fibrosis","volume":"62","author":"Schaupp","year":"2023","journal-title":"Eur. Respir. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.ccm.2022.06.007","article-title":"The Impact of Highly Effective Modulator Therapy on Cystic Fibrosis Microbiology and Inflammation","volume":"43","author":"Caverly","year":"2022","journal-title":"Clin. Chest Med."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Stanton, B.A., Coutermarsh, B., Barnaby, R., and Hogan, D. (2015). Pseudomonas aeruginosa Reduces VX-809 Stimulated F508del-CFTR Chloride Secretion by Airway Epithelial Cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127742"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1007\/s00424-014-1474-6","article-title":"Pseudomonas aeruginosa reduces the expression of CFTR via post-translational modification of NHERF1","volume":"466","author":"Rubino","year":"2014","journal-title":"Pflug. Arch."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"C862","DOI":"10.1152\/ajpcell.00108.2005","article-title":"Pseudomonas aeruginosa inhibits endocytic recycling of CFTR in polarized human airway epithelial cells","volume":"290","author":"Maceachran","year":"2006","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Hirsch, M.J., Hughes, E.M., Easter, M.M., Bollenbecker, S.E., Howze Iv, P.H., Birket, S.E., Barnes, J.W., Kiedrowski, M.R., and Krick, S. (2023). A novel in vitro model to study prolonged Pseudomonas aeruginosa infection in the cystic fibrosis bronchial epithelium. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0288002"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Malet, J.K., Hennemann, L.C., Hua, E.M.L., Faure, E., Waters, V., Rousseau, S., and Nguyen, D. (2022). A Model of Intracellular Persistence of Pseudomonas aeruginosa in Airway Epithelial Cells. Cell. Microbiol., 2022.","DOI":"10.1155\/2022\/5431666"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"IE.9.1","DOI":"10.1002\/cpsc.1","article-title":"Production of 3-D Airway Organoids From Primary Human Airway Basal Cells and Their Use in High-Throughput Screening","volume":"37","author":"Hild","year":"2016","journal-title":"Curr. Protoc. Stem Cell Biol."},{"key":"ref_49","first-page":"183","article-title":"Well-differentiated human airway epithelial cell cultures","volume":"107","author":"Fulcher","year":"2005","journal-title":"Methods Mol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/978-1-62703-125-7_8","article-title":"Human nasal and tracheo-bronchial respiratory epithelial cell culture","volume":"945","author":"Fulcher","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_51","unstructured":"Clinical and Laboratory Standards Institute (2015). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard, Clinical and Laboratory Standards Institute."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Hull-Ryde, E.A., Minges, J.T., Martino, M.E.B., Kato, T., Norris-Drouin, J.L., and Ribeiro, C.M.P. (2021). IRE1alpha Is a Therapeutic Target for Cystic Fibrosis Airway Inflammation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063063"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1128\/JB.00059-15","article-title":"Coculture of Staphylococcus aureus with Pseudomonas aeruginosa Drives S. aureus towards Fermentative Metabolism and Reduced Viability in a Cystic Fibrosis Model","volume":"197","author":"Filkins","year":"2015","journal-title":"J. Bacteriol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1128\/IAI.01373-07","article-title":"In vitro analysis of tobramycin-treated Pseudomonas aeruginosa biofilms on cystic fibrosis-derived airway epithelial cells","volume":"76","author":"Anderson","year":"2008","journal-title":"Infect. Immun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"37955","DOI":"10.1038\/srep37955","article-title":"Hyperglycaemia and Pseudomonas aeruginosa acidify cystic fibrosis airway surface liquid by elevating epithelial monocarboxylate transporter 2 dependent lactate-H(+) secretion","volume":"6","author":"Garnett","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1111\/j.1462-5822.2010.01461.x","article-title":"Infection of human mucosal tissue by Pseudomonas aeruginosa requires sequential and mutually dependent virulence factors and a novel pilus-associated adhesin","volume":"12","author":"Heiniger","year":"2010","journal-title":"Cell. Microbiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1172\/JCI0213870","article-title":"Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients","volume":"109","author":"Worlitzsch","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1164\/ajrccm\/140.6.1650","article-title":"Immunohistopathologic localization of Pseudomonas aeruginosa in lungs from patients with cystic fibrosis. Implications for the pathogenesis of progressive lung deterioration","volume":"140","author":"Baltimore","year":"1989","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1165\/rcmb.2008-0357OC","article-title":"Azithromycin maintains airway epithelial integrity during Pseudomonas aeruginosa infection","volume":"42","author":"Halldorsson","year":"2010","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1089\/jamp.2011.0942","article-title":"Sputum tobramycin concentrations in cystic fibrosis patients with repeated administration of inhaled tobramycin","volume":"26","author":"Ruddy","year":"2013","journal-title":"J. Aerosol Med. Pulm. Drug Deliv."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.2165\/00003495-200363220-00015","article-title":"Inhaled tobramycin (TOBI): A review of its use in the management of Pseudomonas aeruginosa infections in patients with cystic fibrosis","volume":"63","author":"Cheer","year":"2003","journal-title":"Drugs"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1002\/ppul.21011","article-title":"Pseudomonas aeruginosa biofilms in the respiratory tract of cystic fibrosis patients","volume":"44","author":"Bjarnsholt","year":"2009","journal-title":"Pediatr. Pulmonol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e00796-16","DOI":"10.1128\/mBio.00796-16","article-title":"Exposing the Three-Dimensional Biogeography and Metabolic States of Pathogens in Cystic Fibrosis Sputum via Hydrogel Embedding, Clearing, and rRNA Labeling","volume":"7","author":"DePas","year":"2016","journal-title":"mBio"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.jcf.2014.02.004","article-title":"Antibacterial properties of the CFTR potentiator ivacaftor","volume":"13","author":"Reznikov","year":"2014","journal-title":"J. Cyst. Fibros. Off. J. Eur. Cyst. Fibros. Soc."},{"key":"ref_65","first-page":"mgen000981","article-title":"Single nucleotide variants in Pseudomonas aeruginosa populations from sputum correlate with baseline lung function and predict disease progression in individuals with cystic fibrosis","volume":"9","author":"Saber","year":"2023","journal-title":"Microb. Genom."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"11741","DOI":"10.1038\/s41598-023-39005-9","article-title":"Phenotypic and genotypic characteristics of Pseudomonas aeruginosa isolated from cystic fibrosis patients with chronic infections","volume":"13","author":"Iwanska","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"C357","DOI":"10.1152\/ajpcell.00373.2016","article-title":"Effects of Pseudomonas aeruginosa on CFTR chloride secretion and the host immune response","volume":"312","author":"Stanton","year":"2017","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"18703","DOI":"10.1073\/pnas.1422091112","article-title":"pH modulates the activity and synergism of the airway surface liquid antimicrobials beta-defensin-3 and LL-37","volume":"111","author":"Reznikov","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"E6","DOI":"10.1002\/ppul.23971","article-title":"Sensitivity of ivacaftor to drug-drug interactions with rifampin, a cytochrome P450 3A4 inducer","volume":"53","author":"Guimbellot","year":"2018","journal-title":"Pediatr. Pulmonol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1021\/acsinfecdis.6b00035","article-title":"An \u201cUnlikely\u201d Pair: The Antimicrobial Synergy of Polymyxin B in Combination with the Cystic Fibrosis Transmembrane Conductance Regulator Drugs KALYDECO and ORKAMBI","volume":"2","author":"Schneider","year":"2016","journal-title":"ACS Infect. Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1177\/1945892418815615","article-title":"Ivacaftor, a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator, Enhances Ciprofloxacin Activity Against Pseudomonas aeruginosa","volume":"33","author":"Cho","year":"2019","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.ijantimicag.2017.04.014","article-title":"Activity of innate antimicrobial peptides and ivacaftor against clinical cystic fibrosis respiratory pathogens","volume":"50","author":"Payne","year":"2017","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Cigana, C., Giannella, R., Colavolpe, A., Alcala-Franco, B., Mancini, G., Colombi, F., Bigogno, C., Bastrup, U., Bertoni, G., and Bragonzi, A. (2023). Mutual Effects of Single and Combined CFTR Modulators and Bacterial Infection in Cystic Fibrosis. Microbiol. Spectr., 11.","DOI":"10.1128\/spectrum.04083-22"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1172\/JCI73469","article-title":"Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure","volume":"124","author":"Henderson","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"18131","DOI":"10.1073\/pnas.0606428103","article-title":"A physical linkage between cystic fibrosis airway surface dehydration and Pseudomonas aeruginosa biofilms","volume":"103","author":"Matsui","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S1097-2765(01)00286-6","article-title":"The CF salt controversy: In vivo observations and therapeutic approaches","volume":"8","author":"Tarran","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2100185","DOI":"10.1183\/13993003.00185-2021","article-title":"Treatment of cystic fibrosis airway cells with CFTR modulators reverses aberrant mucus properties via hydration","volume":"59","author":"Morrison","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Okuda, K., Shaffer, K.M., and Ehre, C. (2022). Mucins and CFTR: Their Close Relationship. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810232"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1113\/jphysiol.2009.182246","article-title":"Cystic fibrosis transmembrane conductance regulator trafficking modulates the barrier function of airway epithelial cell monolayers","volume":"588","author":"LeSimple","year":"2010","journal-title":"J. Physiol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Simonin, J.L., Luscher, A., Losa, D., Badaoui, M., van Delden, C., Kohler, T., and Chanson, M. (2022). Surface Hydration Protects Cystic Fibrosis Airways from Infection by Restoring Junctional Networks. Cells, 11.","DOI":"10.3390\/cells11091587"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1172\/JCI112708","article-title":"Na+ transport in cystic fibrosis respiratory epithelia. Abnormal basal rate and response to adenylate cyclase activation","volume":"78","author":"Boucher","year":"1986","journal-title":"J. Clin. Investig."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Zhang, L., Button, B., Gabriel, S.E., Burkett, S., Yan, Y., Skiadopoulos, M.H., Dang, Y.L., Vogel, L.N., McKay, T., and Mengos, A. (2009). CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. PLoS Biol., 7.","DOI":"10.1371\/journal.pbio.1000155"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"35751","DOI":"10.1074\/jbc.M505832200","article-title":"Normal and cystic fibrosis airway surface liquid homeostasis. The effects of phasic shear stress and viral infections","volume":"280","author":"Tarran","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.coph.2017.09.013","article-title":"The therapeutic potential of CFTR modulators for COPD and other airway diseases","volume":"34","author":"Solomon","year":"2017","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"190068","DOI":"10.1183\/16000617.0068-2019","article-title":"CFTR targeted therapies: Recent advances in cystic fibrosis and possibilities in other diseases of the airways","volume":"29","author":"Patel","year":"2020","journal-title":"Eur. Respir. Rev."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"17798","DOI":"10.1074\/jbc.M410618200","article-title":"Chronic airway infection\/inflammation induces a Ca2+i-dependent hyperinflammatory response in human cystic fibrosis airway epithelia","volume":"280","author":"Ribeiro","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1801133","DOI":"10.1183\/13993003.01133-2018","article-title":"The Cystic Fibrosis Airway Milieu Enhances Rescue of F508del in a Pre-Clinical Model","volume":"52","author":"Gentzsch","year":"2018","journal-title":"Eur. Respir. J."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"628722","DOI":"10.3389\/fphar.2021.628722","article-title":"Airway Epithelial Inflammation In Vitro Augments the Rescue of Mutant CFTR by Current CFTR Modulator Therapies","volume":"12","author":"Gentzsch","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1002\/ppul.24004","article-title":"Increased cytokines in cystic fibrosis patients\u2019 upper airways during a new P. aeruginosa colonization","volume":"53","author":"Jaudszus","year":"2018","journal-title":"Pediatr. Pulmonol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1136\/thoraxjnl-2017-210298","article-title":"Pseudomonas aeruginosa LasB protease impairs innate immunity in mice and humans by targeting a lung epithelial cystic fibrosis transmembrane regulator-IL-6-antimicrobial-repair pathway","volume":"73","author":"Villeret","year":"2018","journal-title":"Thorax"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/ppul.20010","article-title":"Quantitative cytokine gene expression in CF airway","volume":"37","author":"Muhlebach","year":"2004","journal-title":"Pediatr. Pulmonol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1164\/ajrccm.152.6.8520783","article-title":"Inflammatory cytokines in cystic fibrosis lungs","volume":"152","author":"Bonfield","year":"1995","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1203\/00006450-199308000-00010","article-title":"Interleukin-8 concentrations are elevated in bronchoalveolar lavage, sputum, and sera of children with cystic fibrosis","volume":"34","author":"Dean","year":"1993","journal-title":"Pediatr. Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/22\/2618\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:22:19Z","timestamp":1760131339000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/22\/2618"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,13]]},"references-count":93,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["cells12222618"],"URL":"https:\/\/doi.org\/10.3390\/cells12222618","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,13]]}}}