Modification of development by the CFTR gene in utero.
The in utero infection of rats at 16-17 days gestation with a recombinant adenovirus carrying the human cystic fibrosis transmembrane conductance regulator (cftr) gene resulted in altered lung development and morphology. These structural alterations prompted an evaluation of concurrent functional changes in the cftr-treated lung. CFTR protein could be detected in treated lungs for up to 30 days postinfection, although it was not detected in the intestines at this time. Increased levels of secreted glycoconjugates and lipids were found in lungs treated in utero with human cftr and large vacuoles containing glycoconjugates were detected within cells of the intestines. The scope and durability of these changes suggested that in utero cftr treatment influenced the activity of secretory cells in the developing lung. Altered secretory products in the lungs of cystic fibrosis patients are thought to be associated with increased susceptibility to Pseudomonas aeruginosa infection. We challenged 3-month-old rats (treated in utero with the human cftr gene) with a lethal, intratrachial dose of this bacteria. Rats treated with cftr exhibited enhanced resistance to Pseudomonas infection when compared to controls. These animals displayed little or no associated inflammatory response. No evidence of the adenovirus transgene was detectable at the time of P. aeruginosa inoculation, indicating that continuous ectopic expression of hcftr was not required for enhanced protection. These data demonstrate that in utero, cftr expression influenced the development and function of cells involved in the primary host defense against bacterial infection in the lung.
Morrow
S L
SL
Department of Molecular Genetics, Ochsner Medical Foundation, New Orleans, Louisiana, 70121, USA.
Larson
J E
JE
Nelson
S
S
Sekhon
H S
HS
Ren
T
T
Cohen
J C
JC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000187:drug effects / Q000821:virology; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D007422:Intestines / Q000196:embryology / Q000473:pathology*; D008168:Lung / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D011247:Pregnancy; D011552:Pseudomonas Infections / Q000235:genetics* / Q000473:pathology; D011550:Pseudomonas aeruginosa; D051381:Rats; D017207:Rats, Sprague-Dawley; D019076:Transgenes
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator