RRC ID 65123
著者 Yamazaki R, Kasuya Y, Fujita T, Umezawa H, Yanagihara M, Nakamura H, Yoshino I, Tatsumi K, Murayama T.
タイトル Antifibrotic effects of cyclosporine A on TGF-β1-treated lung fibroblasts and lungs from bleomycin-treated mice: role of hypoxia-inducible factor-1α.
ジャーナル FASEB J
Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder that is characterized by aberrant tissue remodeling and the formation of fibroblastic foci that are composed of fibrogenic myofibroblasts. TGF-β1 is one of the factors that are responsible for fibrosis as it promotes fibroblast to myofibroblast differentiation (FMD) and is associated with up-regulation of α-smooth muscle actin. Therefore, inhibition of FMD may represent an effective strategy for the treatment of IPF. Here, we describe the treatment of human lung fibroblasts (WI-38 and HFL-1 cells) with cyclosporine A (CsA), which reduces TGF-β1-induced FMD via degradation of hypoxia-inducible factor-1α (HIF-1α). In addition, in primary myofibroblast-like cells that were obtained from a patient with pulmonary fibrosis, treatment with CsA and an HIF-1α inhibitor (HIFi) decreased the expression levels of α-smooth muscle actin and fibronectin, which indicated that CsA and HIFi promote dedifferentiation of myofibroblasts. In mice intratracheally administered CsA or HIFi at an early fibrotic stage [7, 8, and 9 d postinstillation (dpi) of bleomycin], marked alleviation of lung fibrosis was observed at 14 dpi. These results suggest that CsA exhibits antifibrotic effects by degrading HIF-1α and that the CsA-HIF-1α axis provides new insights into therapeutic options for the treatment of IPF.-Yamazaki, R., Kasuya, Y., Fujita, T., Umezawa, H., Yanagihara, M., Nakamura, H., Yoshino, I., Tatsumi, K., Murayama, T. Antifibrotic effects of cyclosporine A on TGF-β1-treated lung fibroblasts and lungs from bleomycin-treated mice: role of hypoxia-inducible factor-1α.
巻・号 31(8)
ページ 3359-3371
公開日 2017-8-1
DOI 10.1096/fj.201601357R
PII fj.201601357R
PMID 28446589
MeSH Animals Bleomycin / toxicity Cell Line Cyclosporine / pharmacology* Fibroblasts / drug effects* Humans Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors Hypoxia-Inducible Factor 1, alpha Subunit / genetics Hypoxia-Inducible Factor 1, alpha Subunit / metabolism* Immunosuppressive Agents / pharmacology* Lung / cytology Lung / drug effects Male Mice Mice, Inbred C57BL Pulmonary Fibrosis / chemically induced* Pulmonary Fibrosis / metabolism Transforming Growth Factor beta1 / pharmacology*
IF 4.966
リソース情報
ヒト・動物細胞 WI-38(RCB0702)