title: Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane conductance regulator function and rescue in airway epithelial cells.
abstract: The epithelial response to bacterial airway infection, a common feature of lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis, has been extensively studied. However, its impact on cystic fibrosis transmembrane conductance regulator (CFTR) channel function is not clearly defined. Our aims were, therefore, to evaluate the effect of Pseudomonas aeruginosa on CFTR function and expression in non-cystic fibrosis airway epithelial cells, and to investigate its impact on ΔF508-CFTR rescue by the VRT-325 corrector in cystic fibrosis cells. CFTR expression/maturation was evaluated by immunoblotting and its function by short-circuit current measurements. A 24-h exposure to P. aeruginosa diffusible material (PsaDM) reduced CFTR currents as well as total and membrane protein expression of the wildtype (wt) CFTR protein in CFBE-wt cells. In CFBE-ΔF508 cells, PsaDM severely reduced CFTR maturation and current rescue induced by VRT-325. We also confirmed a deleterious impact of PsaDM on wt-CFTR currents in non-cystic fibrosis primary airway cells as well as on the rescue of ΔF508-CFTR function induced by VRT-325 in primary cystic fibrosis cells. These findings show that CFTR function could be impaired in non-cystic fibrosis patients infected by P. aeruginosa. Our data also suggest that CFTR corrector efficiency may be affected by infectious components, which should be taken into account in screening assays of correctors.
authors: Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada Dept de médecine, Université de Montréal, Montréal, QC, Canada Both authors contributed equally.
authors: Nguyen Thu Ngan
authors: NT
authors: Trinh
authors: Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada Dept de médecine, Université de Montréal, Montréal, QC, Canada Both authors contributed equally.
authors: Claudia
authors: C
authors: Bilodeau
authors: Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
authors: Émilie
authors: É
authors: Maillé
authors: Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada Dept de médecine, Université de Montréal, Montréal, QC, Canada.
authors: Manon
authors: M
authors: Ruffin
authors: Paediatric Otolaryngology Service, Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC, Canada.
authors: Marie-Claude
authors: MC
authors: Quintal
authors: Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
authors: Martin-Yvon
authors: MY
authors: Desrosiers
authors: Meakins-Christie Laboratories, Dept of Medicine, McGill University, Montréal, QC, Canada.
authors: Simon
authors: S
authors: Rousseau
authors: Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada Dept de médecine, Université de Montréal, Montréal, QC, Canada emmanuelle.brochiero@umontreal.ca.
authors: Emmanuelle
authors: E
authors: Brochiero
mesh_terms: D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000150:complications / Q000378:metabolism* / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology; D006801:Humans; D010879:Piperazines / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000150:complications / Q000378:metabolism*; D011550:Pseudomonas aeruginosa; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D055815:Young Adult
chemical_list: C507255:4-cyclohexyloxy-2-(1-(4-(4-methoxy-benzenesulfonyl)piperazin-1-yl)ethyl)quinazoline; C505032:CFTR protein, human; D010879:Piperazines; D011799:Quinazolines; D012333:RNA, Messenger; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator