Abstract
Pulmonary fibrosis is a kind of devastating interstitial lung disease due to the limited therapeutic strategies. Traditional Chinese medicine (TCM) practices have put forth Shenks as a promising treatment approach. Here, we performed in vivo study and in vitro study to delineate the anti-fibrotic mechanisms behind Shenks treatment for pulmonary fibrosis. We found that regardless of the prophylactic or therapeutic treatment, Shenks was able to attenuate BLM-induced-fibrosis in mice, down regulate extracellular matrix genes expression, and reduce collagen production. The aberrantly high Smad3 phosphorylation levels and SBE activity in TGF-β-induced fibroblasts were dramatically decreased as a result of Shenks treatment. At the same time, Shenks was able to increase the expression of antioxidant-related genes, including Gclc and Ec-sod, while reduce the transcription levels of oxidative-related genes, such as Rac1 and Nox4 demonstrated by both in vivo and in vitro studies. Further investigations found that Shenks could decrease the oxidative productions of protein (3-nitrotyrosine) and lipid (malondialdehyde) and increase GSH content both in bleomycin treated mouse lungs and TGF-β stimulated fibroblasts, as well as inhibit the production of ROS stimulated by TGF-β to fight against oxidative stress. Overall, Shenks inhibited fibrosis by blocking TGF-β pathway and modulating the oxidant/antioxidant balance.
Highlights
Pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and interstitial lung fibrosis are severe lung diseases characterized by epithelial injury, impaired wound healing and accumulation of fibroblasts as well as extracellular matrix (ECM) in the lung[1,2,3,4,5]
The results showed that the mRNA level of Col1a2 and Col3a1, the soluble collage protein content determined by Sircol assay and the type I collagen production measured by western blotting were increased significantly by exogenous transforming growth factor (TGF)-β treatment, whereas which were inhibited by Shenks treatment significantly (Supplementary Fig. 3)
The present study demonstrated that no matter whether Shenks was applied prophylactically or therapeutically, it was capable of protecting against bleomycin-induced pulmonary fibrosis in mice, which are comparable to those seen with CYC treatment
Summary
Pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and interstitial lung fibrosis (secondary to conditions such as SSc and rheumatoid arthritis) are severe lung diseases characterized by epithelial injury, impaired wound healing and accumulation of fibroblasts as well as extracellular matrix (ECM) in the lung[1,2,3,4,5]. Some antioxidant agents have the ability to prevent the development of experimental pulmonary fibrosis[18, 19] As it is compatible with the medicinal criteria termed “Jun, Chen, Zuo, Shi”, Shenks is composed of the following active ingredients: Panaxquinquefolius, Ophiopogon japonicas, Salvia miltiorrhizaBge, Gynostemmapentaphyllum (Thunb.) Makino, AmygdalusCommunis Vas, Scutellari + abarbata D. A secondary principal component, was found to exert an anti-fibrotic effect and inhibit experimental skin fibrosis via a TGF-β signaling pathway[24]. The aim of the present study was to explore the mechanism of Shenks’ actions in the treatment of pulmonary fibrosis Both in vivo and in vitro studies were conducted to investigate the treatment effect of Shenks in pulmonary fibrosis, and found that Shenks inhibited fibrosis by blocking TGF-β pathway and balancing of oxidants and antioxidants
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