Rapamycin Inhibits Transforming Growth Factor beta1-Induced Fibrogenesis in Primary Human Lung Fibroblasts.
10.3349/ymj.2013.54.2.437
- Author:
Yu GAO
1
;
Xuefeng XU
;
Ke DING
;
Yan LIANG
;
Dianhua JIANG
;
Huaping DAI
Author Information
1. Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China. daihuaping@sina.com
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
Idiopathic pulmonary fibrosis;
lung fibroblasts;
mTOR pathway;
rapamycin;
transforming growth factor-beta1
- MeSH:
Cells, Cultured;
Collagen Type III/metabolism;
Fibroblasts/*drug effects/metabolism/physiology;
Fibronectins/metabolism;
Humans;
Lung/cytology/drug effects;
Pulmonary Fibrosis/drug therapy;
Signal Transduction/drug effects;
Sirolimus/*pharmacology;
TOR Serine-Threonine Kinases/metabolism/physiology;
Transforming Growth Factor beta1/*antagonists & inhibitors/physiology
- From:Yonsei Medical Journal
2013;54(2):437-444
- CountryRepublic of Korea
- Language:English
-
Abstract:
PURPOSE: The present study was designed to determine whether rapamycin could inhibit transforming growth factor beta1 (TGF-beta1)-induced fibrogenesis in primary lung fibroblasts, and whether the effect of inhibition would occur through the mammalian target of rapamycin (mTOR) and its downstream p70S6K pathway. MATERIALS AND METHODS: Primary normal human lung fibroblasts were obtained from histological normal lung tissue of 3 patients with primary spontaneous pneumothorax. Growth arrested, synchronized fibroblasts were treated with TGF-beta1 (10 ng/mL) and different concentrations of rapamycin (0.01, 0.1, 1, 10 ng/mL) for 24 h. We assessed m-TOR, p-mTOR, S6K1, p-S6K1 by Western blot analysis, detected type III collagen and fibronectin secreting by ELISA assay, and determined type III collagen and fibronectin mRNA levels by real-time PCR assay. RESULTS: Rapamycin significantly reduced TGF-beta1-induced type III collagen and fibronectin levels, as well as type III collagen and fibronectin mRNA levels. Furthermore, we also found that TGF-beta1-induced mTOR and p70S6K phosphorylation were significantly down-regulated by rapamycin. The mTOR/p70S6K pathway was activated through the TGF-beta1-mediated fibrogenic response in primary human lung fibroblasts. CONCLUSION: These results indicate that rapamycin effectively suppresses TGF-beta1-induced type III collagen and fibronectin levels in primary human lung fibroblasts partly through the mTOR/p70S6K pathway. Rapamycin has a potential value in the treatment of pulmonary fibrosis.
