Effect of intratracheal adenoviral vector administration on lung development in newborn rats
| Autor: | Micheline Levame, Chantal Lafuma, Alain Harf, Isabelle Deprez, Marie-Paule Jacob, Marie-Laure Franco-Montoya, Paul Waszak, Christophe Delacourt |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Gene Expression Regulation
Viral Pathology medicine.medical_specialty Recombinant Fusion Proteins Genetic Vectors Bronchi Transfection Andrology Genes Reporter Tropoelastin Parenchyma Genetics medicine Animals Lung volumes RNA Messenger Molecular Biology Lung Inflammation biology Dose-Response Relationship Drug Cell growth Adenoviruses Human Genetic transfer Defective Viruses Epithelial Cells respiratory system Elastic Tissue beta-Galactosidase Proliferating cell nuclear antigen Elastin Rats Trachea Dose–response relationship medicine.anatomical_structure Instillation Drug Animals Newborn biology.protein Molecular Medicine Adenovirus E1A Proteins Lung Volume Measurements Bronchoalveolar Lavage Fluid Immunostaining Cell Division |
| Zdroj: | Human gene therapy. 13(15) |
| ISSN: | 1043-0342 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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