The mechanism of transforming growth factor beta1 in myofibroblast differentiation.
- Author:
Hong-xu LIU
1
;
Si-wen WANG
;
Cheng-hai ZHAO
;
Yang LIU
;
Yu LI
;
Qi-gang ZHANG
;
Wei CONG
;
Xin-gang LAN
;
Shun XU
;
Li-bo HAN
;
Lin ZHANG
Author Information
- Publication Type:Journal Article
- MeSH: Actins; genetics; metabolism; Animals; Blotting, Western; Bronchiolitis Obliterans; genetics; pathology; surgery; Cell Differentiation; drug effects; Cells, Cultured; Disease Models, Animal; Fibroblasts; cytology; drug effects; metabolism; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Knockout; Mitogen-Activated Protein Kinase 1; metabolism; Mitogen-Activated Protein Kinase 3; metabolism; Reverse Transcriptase Polymerase Chain Reaction; Smad3 Protein; genetics; metabolism; Trachea; cytology; transplantation; Transforming Growth Factor beta1; pharmacology; p38 Mitogen-Activated Protein Kinases; metabolism
- From: Chinese Journal of Surgery 2007;45(14):986-989
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVETo investigate the mechanism underlying myofibroblast differentiation induced by transforming growth factor (TGF) beta1 in obliterative bronchiolitis following lung transplantation.
METHODSHeterotopic tracheal transplantation was performed in Smad3 wild-type and knock-out mice to simulate the lung transplantation in human. Murine tracheal fibroblasts cultivated in primary culture were used for in vitro study. Immunohistochemistry, immunocytochemistry, Western Blotting, RT-PCR and DNA electrophoresis mobility gel shift assay were conducted to detect the expression of alpha-smooth muscle actin (alphaSMA), the marker of fibroblast-myofibroblast differentiation, and the activation of Smad3, p38 and ERK1/2.
RESULTSIn affected airways of experimental obliterative bronchiolitis, abundant expression of alphaSMA were found. In vitro study for tracheal fibroblasts, the activation of Smad3 by TGF-beta1 presents as three major forms, phosphorylation, nuclear translocation and DNA binding. In Smad3 wild-type fibroblasts, TGF-beta1 induces the increase of the myofibroblasts transformation, characterized by the elevation of alphaSMA, both at transcription and protein level. While in Smad3 knock-out fibroblasts, the transformation of myofibroblasts induced by TGF-beta1 is significantly decreased (t = 2.080, P = 0.027; t = 1.982, P = 0.032), but not completely abolished. Further study in Smad3-deficient fibroblasts demonstrates that p38 and ERK1/2 could be activated by TGF-beta1 and result in fibroblast differentiation.
CONCLUSIONSTGF-beta1 could promote the transformation of fibroblasts into myofibroblasts in Smad3 dependent and independent signal pathways, especially the Smad3 dependent path, and result in the development of obliterative bronchiolitis.