Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-β Signaling Pathway

Qingmei Liu,Yanyun Ma,Haiyan Chu,Jiucun Wang,Feng Qian,Li Jin,Wenzhen Tu,Xian Ren,Ting Wu,Wenyu Wu,Xiaodong Zhou

doi:10.1038/srep27610

Abstract

Pulmonary fibrosis is a progressive and fatal disorder. In our previous study, we found that the Yiqihuoxue formula (YQHX), a prescription of Traditional Chinese Medicine, had a curative effect on scleroderma, a typical fibrotic disease. The aim of this study was to determine the key ingredient mediating the therapeutic effects of YQHX and to examine its effect on pulmonary fibrosis, including its mechanism. Luciferase reporter assays showed that the most important anti-fibrotic component of the YQHX was Salviae miltiorrhiza (SM). Experiments performed using a bleomycin-instilled mouse model of pulmonary fibrosis showed that Salvianolic acid B (SAB), the major ingredient of SM, had strong anti-inflammatory and anti-fibrotic effects through its inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition. Furthermore, SAB suppressed TGF-β-induced myofibroblastic differentiation of MRC-5 fibroblasts and TGF-β-mediated epithelial-to-mesenchymal transition of A549 cells by inhibiting both Smad-dependent signaling and the Smad-independent MAPK pathway. Taken together, our results suggest that SM is the key anti-fibrotic component of the YQHX and that SAB, the major ingredient of SM, alleviates experimental pulmonary fibrosis both in vivo and in vitro by inhibiting the TGF-β signaling pathway. Together, these results suggest that SAB potently inhibits pulmonary fibrosis.

Highlights

Pulmonary fibrosis represents a group of devastating and largely irreversible disorders characterized by chronic inflammation and excessive deposition of collagen[1,2]
To determine which component in the Yiqihuoxue formula was most important in the inhibition of the Smad-dependent TGF-βpathway, we performed luciferase reporter gene assays using pGL3-SBE4-Luc plasmids, which report binding to Smad-binding element (SBE)
Based on the present data, we considered that Salvia miltiorrhiza (SM) was the most important anti-fibrotic component in Yiqihuoxue formula by down regulation of the TGF-βsignaling pathway

Summary

Introduction

Pulmonary fibrosis represents a group of devastating and largely irreversible disorders characterized by chronic inflammation and excessive deposition of collagen[1,2]. A number of key pro-fibrotic cytokines are responsible for driving the process of fibrogenesis, including transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), and plasminogen activator inhibitor-1 (PAI-1)[6,7]. Among these pro-fibrotic cytokines, TGF-βis considered one of the most potent inducers of fibroblast activation and pulmonary fibrosis pathogenesis. TGF-βcan activate several Smad-independent signaling cascades, including the MAPK pathways, some of which can regulate Smad activation[11]. We found that the anti-pulmonary fibrotic activity of SAB was mediated by inhibition of Smad-dependent and -independent TGF-βsignaling pathways

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Conclusion