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The Anti-Hyperlipidemic Agent Fenofibrate Inhibits TGF-β-Induced Myofibroblast Differentiation and Collagen Production
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A5769 - The Anti-Hyperlipidemic Agent Fenofibrate Inhibits TGF-β-Induced Myofibroblast Differentiation and Collagen Production
Author Block: R. Kikuchi1, Y. Iwai1, T. Tsuji2, K. Yamaguchi3, H. Nakamura1, K. Aoshiba1; 1Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan, 2Dept of Respiratory Medicine, Tokyo Women's Medical University, Institute of Geriatrics, Tokyo, Japan, 3Comprehensive Medical Center of Sleep Disorders, Tokyo Women's Medical University, Tokyo, Japan.
Rationale: Fenofibrate, an anti-hyperlipidemic agent that activates peroxisome proliferator-activated receptor (PPAR) α, has been reported to attenuate fibrosis in the liver, heart and arteries by modulating inflammatory response. Although a previous study with rats showed that treatment with fenofibrate ameliorates pulmonary fibrosis induced by administration of bleomycin, the mechanism underlying the anti-fibrotic effect of fenofibrate remains unclear. In this study, we evaluated the effect of fenofibrate on the behaviors of lung fibroblasts in vitro. Methods: Normal human fetal lung fibroblasts (IMR-90) were grown in Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum (FBS). Upon reaching confluence, cells were serum-starved for 24 hours and then treated with TGF-β (5 ng/ml) in the presence or absence of fenofibrate (25 μM) for up to 72 hours. Then, differentiation of fibroblasts to myofibroblasts was assessed by immunofluorescence with anti-α-smooth muscle actin (α-SMA), western blotting with anti- α-SMA, anti-connective tissue growth factor (CTGF) and anti-collagen type 1 and Sircoll collagen assay for quantification of soluble collagen in the cell culture medium. Results: Treatment of fibroblasts with TGF-β induced myofibroblast differentiation as displayed by increased expression levels of α-SMA, CTGF and collagen type I. However, the presence of fenofibrate inhibited TGF-β-induced expression of α-SMA, CTGF and collagen type I. Conclusions: Fenofibrate attenuated TGF-β-induced myofibroblast differentiation and collagen production. The present study suggests that the anti-fibrotic effect of fenofibrate involves the inhibitory effect on fibroblasts.
Author Block: R. Kikuchi1, Y. Iwai1, T. Tsuji2, K. Yamaguchi3, H. Nakamura1, K. Aoshiba1; 1Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan, 2Dept of Respiratory Medicine, Tokyo Women's Medical University, Institute of Geriatrics, Tokyo, Japan, 3Comprehensive Medical Center of Sleep Disorders, Tokyo Women's Medical University, Tokyo, Japan.
Rationale: Fenofibrate, an anti-hyperlipidemic agent that activates peroxisome proliferator-activated receptor (PPAR) α, has been reported to attenuate fibrosis in the liver, heart and arteries by modulating inflammatory response. Although a previous study with rats showed that treatment with fenofibrate ameliorates pulmonary fibrosis induced by administration of bleomycin, the mechanism underlying the anti-fibrotic effect of fenofibrate remains unclear. In this study, we evaluated the effect of fenofibrate on the behaviors of lung fibroblasts in vitro. Methods: Normal human fetal lung fibroblasts (IMR-90) were grown in Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum (FBS). Upon reaching confluence, cells were serum-starved for 24 hours and then treated with TGF-β (5 ng/ml) in the presence or absence of fenofibrate (25 μM) for up to 72 hours. Then, differentiation of fibroblasts to myofibroblasts was assessed by immunofluorescence with anti-α-smooth muscle actin (α-SMA), western blotting with anti- α-SMA, anti-connective tissue growth factor (CTGF) and anti-collagen type 1 and Sircoll collagen assay for quantification of soluble collagen in the cell culture medium. Results: Treatment of fibroblasts with TGF-β induced myofibroblast differentiation as displayed by increased expression levels of α-SMA, CTGF and collagen type I. However, the presence of fenofibrate inhibited TGF-β-induced expression of α-SMA, CTGF and collagen type I. Conclusions: Fenofibrate attenuated TGF-β-induced myofibroblast differentiation and collagen production. The present study suggests that the anti-fibrotic effect of fenofibrate involves the inhibitory effect on fibroblasts.
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