title: Oxidative stress contributes to the induction and persistence of TGF-β1 induced pulmonary fibrosis.
abstract: Oxidative stress with reactive oxygen species (ROS) can contribute to the pathogenesis of idiopathic pulmonary fibrosis. Antioxidant enzymes, such as extracellular superoxide dismutase (ECSOD), may modulate the injury and repair components of the fibrogenic response. Here we determined whether ECSOD could attenuate experimental TGF-β1-induced persistent lung fibrosis. In this study, primary human lung fibroblasts, MRC-5 fibroblasts and A549 epithelial cells were exposed to recombinant active TGF-β1. An adenovirus vector that expresses human ECSOD (AdECSOD) was constructed and rats were endotracheally intubated with an adenoviral vector encoding active TGF-β1 (AdTGF-β1), AdECSOD or a control vector (AdDL70) alone or in combinations AdTGF-β1/AdDL70 or AdTGF-β1/AdECSOD. TGF-β1 alone induced fibrotic responses and significantly down-regulated endogenous ECSOD gene expression both in vitro and in vivo and caused oxidative stress in rat lung, associated with increased levels of activated TGF-β1 in lung fluid and tissue. ECSOD protein was markedly reduced in the interstitium and fibrotic foci in TGF-β1 induced experimental lung fibrosis. The fibrotic response caused by AdTGF-β1 was markedly attenuated by concomitant gene transfer using AdECSOD, detected by lung function measurements, histologic and morphometric analysis, hydroxyproline content and fibrosis-related gene expression. In addition, the oxidative stress and increased presence of activated TGF-β1 in rat lung induced by AdTGF-β1 was significantly reduced by ECSOD gene transfer. These findings suggest a substantial role for oxidative stress in the pathogenesis of TGF-β1 driven persistent pulmonary fibrosis and enhanced presence of ECSOD can inhibit latent TGF-β1 activation by ROS and diminish subsequent fibrotic responses.
authors.affiliation: Laboratory of Cell Biology and Biochemistry, School of Basic Medical Sciences, Beijing University of Chinese Medicine, Beijing 100029, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Cui
authors.forename: Jennifer
authors.initials: J
authors.lastname: Robertson
authors.forename: Shyam
authors.initials: S
authors.lastname: Maharaj
authors.forename: Lisa
authors.initials: L
authors.lastname: Waldhauser
authors.forename: Jianzhao
authors.initials: J
authors.lastname: Niu
authors.forename: Jifeng
authors.initials: J
authors.lastname: Wang
authors.forename: Laszlo
authors.initials: L
authors.lastname: Farkas
authors.forename: Martin
authors.initials: M
authors.lastname: Kolb
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D013482:Superoxide Dismutase