Oxidative stress contributes to the induction and persistence of TGF-β1 induced pulmonary fibrosis

• Published in: The international journal of biochemistry & cell biology Vol. 43; no. 8; pp. 1122 - 1133
• Main Authors: Cui, Ye, Robertson, Jennifer, Maharaj, Shyam, Waldhauser, Lisa, Niu, Jianzhao, Wang, Jifeng, Farkas, Laszlo, Kolb, Martin, Gauldie, Jack
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.08.2011
• Subjects: Animals; antioxidants; Cells, Cultured; Down-Regulation; epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Fibroblast; fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; fibrosis; gene expression; gene transfer; Humans; hydroxyproline; Interstitial lung disease; Lung - enzymology; Lung - metabolism; Lung - pathology; lung function; morphometry; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Oxidative Stress - physiology; pathogenesis; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Rats; Rats, Sprague-Dawley; reactive oxygen species; Reactive Oxygen Species - metabolism; Recombinant Proteins - pharmacology; Superoxide dismutase; Superoxide Dismutase - biosynthesis; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; TGFβ; Transfection; transforming growth factor beta 1; Transforming Growth Factor beta1 - pharmacology; TGFβ; Oxidative stress; Superoxide dismutase; Interstitial lung disease; Fibroblast
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2011.04.005

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.