Adenovirus-mediated transfer and overexpression of heme oxygenase 1 cDNA in lung prevents bleomycin-induced pulmonary fibrosis via a Fas-Fas ligand-independent pathway.
Heme oxygenase 1 (HO-1) is an inducible enzyme that catalyzes heme to generate bilirubin, ferritin, and carbon monoxide. Because enhanced expression of HO-1 confers protection against many types of cell and tissue damage by modulating apoptotic cell death or cytokine expression profiles, we hypothesized that adenovirus-mediated transfer of HO-1 cDNA and subsequent overexpression of the protein in lung would provide therapeutic benefit in a murine model of bleomycin-induced pulmonary fibrosis. In C57BL/6 mice, HO-1 overexpression clearly suppressed the development of fibrotic changes and was associated with enhanced interferon gamma production in lung and reduced numbers of respiratory epithelial cells with damaged DNA. However, HO-1 overexpression did not prevent pulmonary fibrosis induced by agonistic anti-Fas antibody inhalation in C57BL/6 or ICR mice, a strain known to develop pulmonary fibrosis via the Fas-Fas ligand (FasL) pathway. Consistent with the concept that HO-1 overexpression prevents fibrosis via a pathway independent of Fas-FasL interaction, Ad.HO-1 administration prevented bleomycin-induced pulmonary fibrosis in gld/gld mice, which express nonfunctional FasL. These observations suggest that using HO-1 overexpression strategies to treat idiopathic pulmonary fibrosis, or fibrotic disorders of other target organs, by attenuating apoptotic cell death likely would be effective in clinical situations.
Tsuburai
Takahiro
T
First Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.
Suzuki
Motoyoshi
M
Nagashima
Yoji
Y
Suzuki
Shunsuke
S
Inoue
Satoshi
S
Hasiba
Tomonori
T
Ueda
Atsuhisa
A
Ikehara
Kunihiko
K
Matsuse
Takeshi
T
Ishigatsubo
Yoshiaki
Y
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D001761:Bleomycin / Q000494:pharmacology*; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D053222:Fas Ligand Protein; D005355:Fibrosis; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000235:genetics*; D051547:Heme Oxygenase-1; D006909:Hydroxyproline / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008024:Ligands; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D015398:Signal Transduction; D013997:Time Factors
D018076:DNA, Complementary; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D001761:Bleomycin; D004247:DNA; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D006909:Hydroxyproline