Gene complementation of airway epithelium in the cystic fibrosis mouse is necessary and sufficient to correct the pathogen clearance and inflammatory abnormalities

Delvac Oceandy; Brendan J McMorran; Stephen N Smith; Rainer Schreiber; Karl Kunzelmann; Eric W F W Alton; David A Hume; Brandon J Wainwright

doi:10.1093/hmg/11.9.1059

Gene complementation of airway epithelium in the cystic fibrosis mouse is necessary and sufficient to correct the pathogen clearance and inflammatory abnormalities

Hum Mol Genet. 2002 May 1;11(9):1059-67. doi: 10.1093/hmg/11.9.1059.

Authors

Delvac Oceandy¹, Brendan J McMorran, Stephen N Smith, Rainer Schreiber, Karl Kunzelmann, Eric W F W Alton, David A Hume, Brandon J Wainwright

Affiliation

¹ Institute for Molecular Biosciences, Imperial College of Medicine at the National Heart and Lung Institute, Manresa Road, London SW3 6LR, UK.

PMID: 11978765
DOI: 10.1093/hmg/11.9.1059

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Methyl-3-isobutylxanthine / pharmacology
Animals
Bronchoalveolar Lavage
Cells, Cultured
Chemokine CXCL2
Colforsin / pharmacology
Cystic Fibrosis / metabolism*
Cystic Fibrosis / microbiology
Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
Electrophysiology
Enzyme-Linked Immunosorbent Assay
Epithelial Cells / metabolism
Epithelial Cells / microbiology
Female
Fluorescent Antibody Technique
Genetic Complementation Test
Humans
Lung / cytology
Macrophages, Alveolar / metabolism
Macrophages, Alveolar / microbiology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Monokines / metabolism
Mutation / genetics
Phosphodiesterase Inhibitors / pharmacology
Pseudomonas Infections / metabolism*
Pseudomonas Infections / microbiology
Pseudomonas aeruginosa / physiology*
RNA, Messenger / metabolism
Tumor Necrosis Factor-alpha / metabolism

Substances

CFTR protein, human
Chemokine CXCL2
Monokines
Phosphodiesterase Inhibitors
RNA, Messenger
Tumor Necrosis Factor-alpha
Cystic Fibrosis Transmembrane Conductance Regulator
Colforsin
1-Methyl-3-isobutylxanthine