Journal
BIOMEDICINE & PHARMACOTHERAPY
Volume 121, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2019.109586
Keywords
Tanshinone IIA; Silicosis; Pulmonary fibrosis; Transforming growth factor-beta 1; Smad
Funding
- National natural science foundation of China [81473485, 81973630]
- Natural Science Foundation of Shandong Province [2014ZRE27321]
- Shandong University Interdisciplinary Training Project [2017JC028]
- Jinan Medical and Health Science and Technology Innovation Plan [201704069]
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Transforming growth factor-beta 1 (TGF-beta 1) is a key mediator in fibrogenesis, and is upregulated and activated in fibrotic diseases. The exact role of TGF-beta 1-Smad signaling in the progression of silicosis fibrosis is yet to be conclusively determined. Using a Wistar rat silicosis model, we examined whether tanshinone IIA (Tan IIA) could meliorate silicosis fibrosis. The pulmonary fibroblasts of rats from the normal control group and silicosis-induced model group were extracted and examined so as to further explore the disruption of TGF-beta 1-Smad signaling pathway in silicosis pathogenesis and the intervention of Tan IIA in this pathway. Using RT-PCR, immunohistochemical staining, and immunofluorescence analysis, we determined that Tan IIA could ameliorate silicosis fibrosis, downregulate collagen I, collagen III, and alpha-SMA expression both, in vivo and in vitro. In silicosis fibroblasts, TGF-beta 1 induced phosphorylation of Smad2, Smad3, and negative feedback Smad7 inhibition in a dose dependent manner, and the phosphorylation of Smad3 persisted when the upstream signal was blocked. Tan IIA treatment effectively inhibited the TGF-beta 1-induced phosphorylation of Smads, especially the persistent phosphorylation of Smad3 in the nucleus, and upregulated the expression of Smad7 in silicosis fibroblasts, leading to a reduction in ECM deposition. Our findings indicate that dysregulation of the TGF-beta 1-Smad signaling pathway may play an important role in the pathological process of silicosis. Tan IIA thus ameliorates silicosis fibrosis partially by suppressing activation of TGF-beta 1-Smad signaling pathway, which may turn out to be a potential therapeutic approach to prevent silicosis fibrosis.
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