Effects of bronchopulmonary inflammation induced by pseudomonas aeruginosa on adenovirus-mediated gene transfer to airway epithelial cells in mice.
Cystic fibrosis (CF) patients have endobronchial inflammation caused by infection with mucoid Pseudomonas aeruginosa. Since adenovirus vectors are being studied for gene therapy for CF, we sought to determine whether bronchopulmonary inflammation would influence adenovirus-mediated gene transfer. We hypothesized that bronchopulmonary inflammation in mice inoculated with mucoid P. aeruginosa would be associated with a decrease in the efficacy of adenovirus-mediated gene transfer. Agarose beads embedded with mucoid P. aeruginosa (6 x 10(4) c.f.u. per mouse) were inoculated transtracheally into C57BL/6 mice. Control mice received sterile agarose beads. Ten days after inoculation with agarose beads, recombinant adenovirus containing the beta-galactosidase reporter gene (Ad2/beta Gal-2) was administered intranasally (1.1 x 10(9) IU per mouse), and mice were killed 3 days later. The extent of inflammation, determined by neutrophil numbers in bronchoalveolar lavage fluid and by areal lung inflammation, was significantly greater in mice inoculated with P. aeruginosa-laden agarose beads and Ad2/beta Gal-2 compared with controls. Mice that had received Pseudomonas-laden agarose beads and Ad2/beta Gal-2 had significantly fewer (P < 0.015) airway epithelial cells transduced (4.1 +/- 0.9%) compared with mice that received sterile agarose beads and Ad2/beta Gal-2 (9.4 +/- 1.4%). These results indicate that the efficacy of adenovirus-mediated gene transfer is reduced in Pseudomonas-induced bronchopulmonary inflammation.
van Heeckeren
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Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Childrens Hospital, Cleveland, OH, USA.
Ferkol
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Tosi
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D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D002908:Chronic Disease; D003550:Cystic Fibrosis / Q000150:complications / Q000473:pathology / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009894:Opportunistic Infections / Q000150:complications / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000150:complications* / Q000473:pathology; D011552:Pseudomonas Infections / Q000150:complications* / Q000473:pathology; D015431:Weight Loss