Effect of intratracheal adenoviral vector administration on lung development in newborn rats

• Published in: Human gene therapy Vol. 13; no. 15; p. 1873
• Main Authors: Waszak, Paul, Franco-Montoya, Marie-Laure, Jacob, Marie-Paule, Deprez, Isabelle, Levame, Micheline, Lafuma, Chantal, Harf, Alain, Delacourt, Christophe
• Format: Journal Article
• Language: English
• Published: United States 10.10.2002
• Subjects: Adenovirus E1A Proteins - deficiency; Adenovirus E1A Proteins - physiology; Adenoviruses, Human - genetics; Adenoviruses, Human - physiology; Animals; Animals, Newborn; beta-Galactosidase - biosynthesis; beta-Galactosidase - genetics; Bronchi - pathology; Bronchi - virology; Bronchoalveolar Lavage Fluid; Cell Division; Defective Viruses - genetics; Defective Viruses - physiology; Dose-Response Relationship, Drug; Elastic Tissue - pathology; Elastin - metabolism; Epithelial Cells - pathology; Gene Expression Regulation, Viral; Genes, Reporter; Genetic Vectors - pharmacology; Genetic Vectors - toxicity; Inflammation; Instillation, Drug; Lung - metabolism; Lung - pathology; Lung - virology; Lung Volume Measurements; Rats; Recombinant Fusion Proteins - biosynthesis; RNA, Messenger - biosynthesis; Trachea; Transfection; Tropoelastin - biosynthesis; Tropoelastin - genetics
• ISSN: 1043-0342
• DOI: 10.1089/104303402760372963

Local overexpression of genes that promote lung defense or repair may be helpful in protecting the immature neonatal lung from injuries, but whether the vectors used to administer these genes affect physiological postnatal lung growth has not been investigated. We explored the effect on alveolarization of E1-deleted Adnull vector (Ad5-LMP-null) given intratracheally to 3-day-old rats. Three Adnull doses were evaluated 10(8), 5 x 10(8), and 10(9) TCID(50). Lung morphometry on day 21 showed significant growth disorders with the two higher doses. With 5 x 10(8) TCID(50), absolute lung volume increased significantly (+16%), as did absolute (+20%) and specific (+32%) alveolar airspace volumes, whereas alveolar surface density decreased by 13% (p < 0.009 for all parameters). Lung inflammation was mild, nonsignificant, and occurred mainly with the highest Adnull dose, indicating that it was unlikely to contribute to our results. Adnull instillation induced a significant#10; decrease in terminal bronchiolar cell proliferation as evaluated by proliferating cell nuclear antigen immunostaining (p = 0.02), as well as a 23% decrease in absolute parenchyma elastic fiber length (p = 0.02). Furthermore, lung tropoelastin mRNA content decreased by 25% (p < 0.02). In conclusion, E1-deleted adenoviral vectors can induce lung growth disorders when instilled into the airways of neonatal rats. Interactions with lung matrix turnover may be the main explanation to these deleterious effects.