N-acetyl-l-cysteine inhibits TGF-β₁-induced profibrotic responses in fibroblasts

Background: Excessive production of TGF-β₁ 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-β₁ has been reported to decrease the intracellular glutathione level and stimulate the production of reactive oxygen species. Objectives: The aim of this study was to evaluate whether the antioxidant N-acetyl-l-cysteine (NAC) can affect TGF-β₁-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-β₁-mediated contraction of floating gels and the TGF-β₁-induced mediator production. In addition, the effect of NAC on the TGF-β₁-induced differentiation to myofibroblasts was evaluated by assessing α-smooth muscle actin (α-SMA) expression. Results: NAC significantly abolished the TGF-β₁-augmented gel contraction (at 3 mM, 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-β₁-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-β₁-stimulated α-SMA expression (p < 0.01). Conclusion: These results suggest that NAC can affect the TGF-β₁-induced tissue remodeling or fibrotic process in vitro.