title: Gene complementation of airway epithelium in the cystic fibrosis mouse is necessary and sufficient to correct the pathogen clearance and inflammatory abnormalities.
abstract: Increasingly, cystic fibrosis (CF) is regarded as an inflammatory disorder where the response of the lung to Pseudomonas aeruginosa is exaggerated as a consequence of processes mediated by the product of the CF gene, CFTR. Of importance to any gene-replacement strategy for treatment of CF is the identification of the cell type(s) within the lung milieu that need to be corrected and an indication whether this is sufficient to restore a normal inflammatory response and bacterial clearance. We generated G551D CF mice transgenically expressing the human CFTR gene in two tissue compartments previously demonstrated to mediate a CFTR-dependent inflammatory response: lung epithelium and alveolar macrophages. Following chronic pulmonary infection with P. aeruginosa, CF mice with epithelial-expressed but not macrophage-specific CFTR showed an improvement in pathogen clearance and inflammatory markers compared with control CF animals. Additionally, these data indicate the general role for epithelial cell-mediated events in the response of the lung to bacterial pathogens and the importance of CFTR in mediating these processes.
authors.affiliation: Institute for Molecular Biosciences, Imperial College of Medicine at the National Heart and Lung Institute, Manresa Road, London SW3 6LR, UK.
authors.forename: Delvac
authors.initials: D
authors.lastname: Oceandy
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: McMorran
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Smith
authors.forename: Rainer
authors.initials: R
authors.lastname: Schreiber
authors.forename: Karl
authors.initials: K
authors.lastname: Kunzelmann
authors.forename: Eric W F W
authors.initials: EW
authors.lastname: Alton
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Wainwright
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D018893:Bronchoalveolar Lavage; D002478:Cells, Cultured; D054426:Chemokine CXCL2; D005576:Colforsin / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D004594:Electrophysiology; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D005260:Female; D005455:Fluorescent Antibody Technique; D005816:Genetic Complementation Test; D006801:Humans; D008168:Lung / Q000166:cytology; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015846:Monokines / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000378:metabolism* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; D054426:Chemokine CXCL2; D015846:Monokines; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D015056:1-Methyl-3-isobutylxanthine