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: Nguyen Thu Ngan Trinh, Claudia Bilodeau, Émilie Maillé, Manon Ruffin, Marie-Claude Quintal, Martin-Yvon Desrosiers, Simon Rousseau, Emmanuelle Brochiero
• Journal: The European respiratory journal (Eur Respir J) Vol. 45 Issue 6 Pg. 1590-602 (Jun 2015) ISSN: 1399-3003 [Electronic] England
• PMID: 25792634 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright ©ERS 2015.

Chemical References

• 4-cyclohexyloxy-2-(1-(4-(4-methoxy-benzenesulfonyl)piperazin-1-yl)ethyl)quinazoline
• CFTR protein, human
• Piperazines
• Quinazolines
• RNA, Messenger
• cystic fibrosis transmembrane conductance regulator delta F508
• Cystic Fibrosis Transmembrane Conductance Regulator

Topics

• Cells, Cultured
• Cystic Fibrosis (complications, metabolism, microbiology)
• Cystic Fibrosis Transmembrane Conductance Regulator (drug effects, genetics, metabolism)
• Epithelial Cells (metabolism, microbiology)
• Humans
• Piperazines (pharmacology)
• Pseudomonas Infections (complications, metabolism)
• Pseudomonas aeruginosa
• Quinazolines (pharmacology)
• RNA, Messenger (metabolism)
• Respiratory Mucosa (cytology, metabolism, microbiology)
• Young Adult