Keratinocyte growth factor gene transduction ameliorates pulmonary fibrosis induced by bleomycin in mice.
Pulmonary fibrosis has high rates of mortality and morbidity, but there is no established therapy at present. We demonstrate here that bleomycin-induced pulmonary fibrosis in mice is ameliorated by intratracheal administration of keratinocyte growth factor (KGF)-expressing adenovirus vector. Progressive pulmonary fibrosis was created by continuous subcutaneous administration of 120 mg/kg of bleomycin subcutaneously using an osmotic pump twice from Day 1 to 7 and Day 29 to 35. The mice initially exhibited subpleural fibrosis and then exhibited advanced fibrosis in the parenchyma of the lungs. These histopathological changes were accompanied by reduced lung compliance (0.041 ± 0.011 versus 0.097 ± 0.004; P < 0.001), reduced messenger expression of surfactant proteins, and reduced KGF messenger expression in the lungs at 4 weeks compared with naive group. Intratracheal instillation of Ad-KGF at 1 week after the first administration of bleomycin increased KGF mRNA expression in the lungs compared with the fibrosis-induced mice that received saline alone. The phenotype was associated with alveolar epithelial cell proliferation, increased pulmonary compliance (0.062 ± 0.005 versus 0.041 ± 0.011; P = 0.023), and decreased mortality (survival rate on Day 56: 68.8% versus 0%; P = 0.002), compared with mice receiving only the saline vehicle. These observations suggest the therapeutic utility of a KGF-expressing adenoviral vector for pulmonary fibrosis.
Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
Seiko
S
Sakamoto
Takuya
T
Yazawa
Yasuko
Y
Baba
Hanako
H
Sato
Yumi
Y
Kanegae
Toyohiro
T
Hirai
Izumu
I
Saito
Takahisa
T
Goto
Kiyoyasu
K
Kurahashi
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology*; D049109:Cell Proliferation; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D008168:Lung / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D037663:Pulmonary Surfactant-Associated Protein D / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013501:Surface-Active Agents / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D037663:Pulmonary Surfactant-Associated Protein D; D012333:RNA, Messenger; D013501:Surface-Active Agents; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D051523:Fibroblast Growth Factor 7