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1 Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
2 Department of Molecular Biology, Genzyme Corporation, Framingham, MA, USA
3 Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
* To whom correspondence should be addressed. E-mail: amv2{at}cwru.edu.
In cystic fibrosis there is an excessive inflammatory response to lung infections with Pseudomonas aeruginosa, which causes significant morbidity and mortality. Mice deficient in the cystic fibrosis conductance transmembrane regulator homologue (Cftr) have exaggerated production of pro-inflammatory cytokines in epithelial lining fluid, and increased mortality in response to chronic bronchopulmonary infection with mucoid Pseudomonas aeruginosa, compared to infected wildtype littermates. Whether delivery of CFTR to cystic fibrosis airways by an adenoviral vector (Ad2/CFTR-16) decreases cytokine production and mortality in response to chronic bronchopulmonary infection with mucoid Pseudomonas aeruginosa was tested. Cystic fibrosis mice (STOCK Cftrtm1Unc-TgN(FABPCFTR)#Jaw) were anesthetized with isoflurane and inoculated intranasally with either Ad2/CFTR-16, or diluent (sucrose), or empty vector (Ad2/EV). Two weeks later mice were anesthetized with 2.5% Avertin and inoculated transtracheally with P. aeruginosa-laden agarose beads (PA M57-15). The cumulative ten-day survival of mice pretreated with Ad2/CFTR-16 (48.3%; n=29) was significantly higher (P = 0.0188) compared to mice pretreated with sucrose (18.5%; n=27) but not significantly higher (P = 0.13) than mice pretreated with Ad2/EV (28.0%; n = 25). After adjusting for differences in experiment, weight loss at 3 days for mice treated with Ad2/CFTR-16 was significantly less than for the sucrose- or Ad2/EV-treated groups (P-values = 0.005 and 0.009, respectively). However, cytokine responses were similar in all groups three days after infection. In conclusion, the observed survival advantage of adenoviral delivery of CFTR to the cystic fibrosis lung may be due to either CFTR expression or to possibly pro-inflammatory effects of the adenoviral vector, or both.
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