Adenovirus-mediated fibroblast growth factor 1 expression in the lung induces epithelial cell proliferation: consequences to hyperoxic lung injury in rats.
High concentrations of oxygen can induce pulmonary toxicity and cause injury to alveolar epithelial and endothelial cells. The present study was performed to determine whether the potent epithelial and endothelial fibroblast growth factor 1 (FGF-1) protected against hyperoxia-induced lung injury. Recombinant adenovirus carrying the gene encoding human secreted FGF-1 (Ad. FGF1) increased the proliferation of lung epithelial cells in vitro. Ad.FGF1 or control vector with an empty expression cassette (Ad.V152) was administered intratracheally to Wistar rats. With Ad.FGF1 (10(9), 5 x 10(9), 10(10), or 5 x 10(10) viral particles [VP]), FGF-1 protein was found in bronchoalveolar lavage fluid 4 days postinfection at levels proportional to the viral dose and was detected in plasma after doses of 10(10) VP or more were administered. Histological examination of the lungs showed intense proliferation and apoptosis of alveolar and bronchial epithelial cells, with few inflammatory cells. The alveolar architecture returned to normal within 17 days. Rats pretreated with Ad.FGF1 (10(9) or 5 x 10(9) VP) 2 days before exposure to hyperoxia (95% O2) survived, whereas rats pretreated with Ad.V152 died within 3 days. In conclusion, adenovirus-mediated FGF-1 overexpression in the lungs causes epithelial cell proliferation and has beneficial effects in hyperoxic lung injury.
Physiology Department, National Institute for Health and Medical Research (INSERM) Unit 492, Henri Mondor Teaching Hospital, AP-HP, 94010 Créteil, France.
Vanessa
V
Louzier
William
W
Raoul
Aude
A
Leroux
Didier
D
Branellec
Jean-Michel
JM
Caillaud
Hélène
H
Many
Micheline
M
Levame
Christophe
C
Delclaux
Serge
S
Adnot
Bernard
B
Maitre
D000256:Adenoviridae / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004847:Epithelial Cells / Q000166:cytology*; D016220:Fibroblast Growth Factor 1 / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000648:ultrastructure; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008854:Microscopy, Electron; D010100:Oxygen / Q000009:adverse effects*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D018809:Proliferating Cell Nuclear Antigen; D016220:Fibroblast Growth Factor 1; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D010100:Oxygen