The Protective Role of Tanshinone IIA in Silicosis Rat Model via TGF-β1/Smad Signaling Suppression, NOX4 Inhibition and Nrf2/ARE Signaling Activation

Abstract

Purpose

Silicosis is an occupational disease caused by inhalation of silica and there are no effective drugs to treat this disease. Tanshinone IIA (Tan IIA), a traditional natural component, has been reported to possess anti-inflammatory, antioxidant, and anti-fibrotic properties. The current study’s purpose was to examine Tan IIA’s protective effects against silica-induced pulmonary fibrosis and to explore the underlying mechanisms.

Methods

48 male SD rats were randomly divided into four groups (n=12): i) Control group; ii) Silicosis group; iii) Tan IIA group; iv) Silicosis +Tan IIA group. Two days after modeling, the rats of Tan IIA group and Silicosis +Tan IIA group were given intraperitoneal administration 25 mg/kg/d Tan IIA for 40 days. Then, the four groups of rats were sacrificed and the lung inflammatory responses were measured by ELISA, lung damage and fibrosis were analyzed by hematoxylin and eosin (H&E) staining and Masson staining, the expression levels of collagen I, fibronectin and α-smooth muscle actin (α-SMA) were measured by immunohistochemistry. The markers of oxidative stress were measured by commercial kits, and the activity of the TGF-β1/Smad and NOX4, Nrf2/ARE signaling pathways were measured by RT-PCR and Western blotting.

Results

The silica-induced pulmonary inflammtory responses, structural damage and fibrosis were significantly attenuated by Tan IIA treatment. In addition, treatment with Tan IIA decreased collagen I, fibronectin and α-SMA expression, and inhibited TGF-β1/Smad signaling in the lung tissue. The upregulated levels of oxidative stress markers in silicosis rats were also markedly restored following Tan IIA treatment. Furthermore, treatment with Tan IIA reduced NOX4 expression and enhanced activation of the Nrf2/ARE pathway in the lung tissue of silicosis rats.

Conclusion

These findings suggest that Tan IIA may protect lung from silica damage via the suppression of TGF-β1/Smad signaling, inhibition of NOX4 expression and activation of the Nrf2/ARE pathway.

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Keywords:

• silicosis
• tanshinone IIA
• TGF-β1/Smad
• NOX4
• Nrf2/ARE

Ethics Approval and Consent to Participate

All of the animal procedures, including housing, care and experimental protocols, were approved by the Scientific Research Ethics Committee of the Second Hospital of Shandong University (Permit Number: 20140195).

Availability of Data and Materials

All data generated or analyzed during this study are included in this published article.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

The present study was supported by the National Natural Science Foundation of China (grant no. 81473485 and 81973630), the Natural Science Foundation of Shandong Province (grant no. 2014ZRE27321), Shandong University Interdisciplinary Training Project (grant no. 2017JC028), and the Jinan Medical and Health Science and Technology Innovation Plan (grant no. 201704069).