N-acetyl-L-cysteine inhibits TGF-beta1-induced profibrotic responses in fibroblasts.
BACKGROUND
Excessive production of TGF-beta(1) plays a key role in the tissue remodeling or fibrotic process observed in bronchial asthma, chronic pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). TGF-beta(1) has been reported to decrease the intracellular glutathione level and stimulate the production of reactive oxygen species.


OBJECTIVE
The aim of this study was to evaluate whether the antioxidant N-acetyl-l-cysteine (NAC) can affect TGF-beta(1)-mediated tissue remodeling in fibroblasts or modulate the production of fibronectin and vascular endothelial growth factor (VEGF) which are believed to be important mediators of tissue repair and remodeling.


METHODS
To accomplish this, human fetal lung fibroblasts (HFL-1) were used to assess the effect of NAC on the TGF-beta(1)-mediated contraction of floating gels and the TGF-beta(1)-induced mediator production. In addition, the effect of NAC on the TGF-beta(1)-induced differentiation to myofibroblasts was evaluated by assessing alpha-smooth muscle actin (alpha-SMA) expression.


RESULTS
NAC significantly abolished the TGF-beta(1)-augmented gel contraction (at 3mM, gel size 63.4+/-2.6% vs. 39.1+/-4.1%; p<0.01) compared with control in a concentration-dependent manner. NAC also significantly inhibited the TGF-beta(1)-augmented fibronectin (p<0.01) and VEGF (p<0.01) production in the media of both the three-dimensional gel and monolayer culture. Furthermore, NAC reversed the TGF-beta(1)-stimulated alpha-SMA expression (p<0.01).


CONCLUSIONS
These results suggest that NAC can affect the TGF-beta(1)-induced tissue remodeling or fibrotic process in vitro.
Sugiura
Hisatoshi
H
Third Department of Internal Medicine, Wakayama Medical University School of Medicine, 811-1 Kimiidera, Wakayama, Wakayama 641-0012, Japan. sugiura@wakayama-med.ac.jp
Ichikawa
Tomohiro
T
Liu
Xiangde
X
Kobayashi
Tetsu
T
Wang
Xing Qi
XQ
Kawasaki
Shin
S
Togo
Shinsaku
S
Kamio
Koichiro
K
Mao
Lijun
L
Ann
Youngsoo
Y
Ichinose
Masakazu
M
Rennard
Stephen I
SI
D000111:Acetylcysteine / Q000494:pharmacology*; D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D024042:Collagen Type I / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology*; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics; D005355:Fibrosis; D006801:Humans; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D000199:Actins; D024042:Collagen Type I; D005353:Fibronectins; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D000111:Acetylcysteine