Toxicity of fiber- and penton base-modified adenovirus type 5 vectors on lung development in newborn rats.
Transient overexpression of genes involved in lung regulation might prevent alveolar developmental disorders (ADDs) in premature neonates. However, adenovirus 5 (Ad5) vectors per se, and not isolated capsid proteins, induce ADDs after tracheal administration to newborn rats. To test the hypothesis that Ad5 capsid components are mainly responsible for ADDs, we evaluated newborn rats' lung development by morphometry after tracheal administration of a panel of Ad5 vectors with mutations in the fiber or penton base. Three distinct patterns of lung response were observed on postnatal day (PD) 21: (i) emphysematous-like lesions, common to Ad5 overexposing RGD motifs; (ii) altered septation, representative of the wild-type capsid Ad5 lesion; (iii) absence of lung toxicity, shown by Ad5 vectors with fibers shortened to seven repeats. None of these patterns correlated with the degree of lung inflammation or gene transduction. In contrast, a more impaired elastogenesis associated with emphysema was preceded by a significantly increased level of activated caspase 3 on PD11. Moreover, the altered septation was associated with a persistent and significant increase in terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive alveolar septal cells on PD21. Our results underline the deleterious effects of Ad-induced apoptosis, which is not only responsible for limited transgene expression but also involved in lung development disorders.
Waszak
Paul
P
Laboratoire de Virologie et Pathologie Humaine, CNRS FRE 3011, Université de Lyon, Faculté de Médecine RTH Laënnec, Lyon, France. paul.waszak@univ-lyon1.fr
Franqueville
Laure
L
Franco-Motoya
Marie-Laure
ML
Rosa-Calatrava
Manuel
M
Boucherat
Olivier
O
Lindholm
Leif
L
Delacourt
Christophe
C
Boulanger
Pierre
P
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D048430:Cell Shape; D005822:Genetic Vectors / Q000235:genetics* / Q000633:toxicity*; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000166:cytology* / Q000254:growth & development*; D011014:Pneumonia / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic
D036022:Capsid Proteins; C043322:penton protein, adenovirus; D053148:Caspase 3