Sodium tanshinone IIA sulfonate attenuates silica-induced pulmonary fibrosis in rats via activation of the Nrf2 and thioredoxin system
Introduction
Silicosis is characterized by progressive deterioration of pulmonary function and irreversible fibrosis resulting from inhalation of silica particles. Although silicosis occurs globally, it remains the most serious occupational disease among workers engaged in the mining, construction, and manufacturing industries in many developing countries. China is the country with the largest number of silicosis patients around the world. Silicosis not only seriously damages patient health and quality of life but also imposes a heavy burden on both society and families. Unfortunately, there are currently no effective treatments for silicosis.
The traditional Chinese medicine Danshen, derived from the dried root or rhizome of Salviae miltiorrhizae Bge, has been widely used for the treatment of cardiovascular and cerebrovascular diseases. Tanshinone IIA (Tan-IIA) is structurally representative of the tanshinones of Salvia miltiorrhiza and is also the most abundant form(Yang et al., 2009). Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative formed by the sulfonation of Tan-IIA. The introduction of sulfonic acid groups into STS considerably improved its water solubility and efficacy in the treatment of coronary heart disease, angina pectoris, and myocardial infarction. Thus, STS is now considered to be therapeutically superior to Tan-IIA. In recent years, many studies have reported that STS improves the microcirculation and inhibits the release of inflammatory mediators and ROS (Yan et al., 2018). A recent study has found that STS prevent angiotensin II-induced differentiation of atrial fibroblasts to myofibroblasts through suppressing oxidative stress and inhibiting the activation of TGF-β1 signaling pathway (Chen et al., 2018). Our previous studies also showed that STS inhibited oxidative stress and activation of embryonic lung fibroblasts after exposure to silica in vitro (Zhu et al., 2016). However, little is currently known about the anti-fibrotic effects of STS and its molecular mechanisms of action in silica-induced pulmonary fibrosis.
The transcription factor nuclear factor erythroid 2-related factor 2 (NFE2L2, abbreviated to Nrf2) is essential for the cellular response to ROS and oxidative stress. Nrf2 belongs to the Cap ‘n’ Collar subfamily of basic-region leucine zipper transcription factors. When oxidative stress occurs, Nrf2 translocates to the nucleus and binds to antioxidant response elements to upregulate the transcription of genes involved in the regulation of metabolism, proteostasis, and redox balance(Patinen et al., 2019). Cho et al. observed that Nrf2−/− mice were more susceptible than wild-type mice to bleomycin-induced inflammation and pulmonary fibrosis(Cho et al., 2004). The antioxidant function of the endogenous thioredoxin (Trx) system has attracted increasing attention for its role in disease pathology. Trx is a small protein containing a conserved cystine-glycine-proline-cysteine-disulfide active site sequence(Holmgren and Lu, 2010). Together with reduced nicotine adenine dinucleotide phosphate, Trx and Trx reductase (TrxR), which is the only known physiological reductant of Trx, constitute the “Trx system”(Lu and Holmgren, 2014). The system maintains intracellular and extracellular redox balance through a disulfide–thiol exchange reaction and thus plays an important role in the cellular response to oxidative stress(Matsuzawa, 2017). Nrf2 has been shown to directly regulate the transcription of TrxR during the adaptive oxidative stress response in human or mammalian cells, thereby enhancing their survival(Tonelli et al., 2018). However, the relationship between Nrf2 and Trx in other tissues and cells is less studied, as is its involvement in silicosis.
In the present study, we employed a rat model of silicosis previously established in our lab to explore the effects of STS intervention on oxidative stress levels and the progression of pulmonary fibrosis. We also uncovered a novel relationship between Nrf2 and its target proteins Trx/TrxR and shed light on the contribution of the Nrf2/Trx/TrxR axis to the therapeutic efficacy of STS in silicosis.
Section snippets
Silica particles and STS
The crystalline silica particles were purchased from Sigma-Aldrich Co. LLC. The morphology of the silica particles was assessed by scanning electron microscopy (SEM, HITACHI, S-4800) and transmission electron microscopy (TEM, JEOL, JEM-2100) (Fig. 1A&B). The dispersion of silica particles was measured by granulometer (Malvern Nano-ZS90, Britain) (Fig. 1C). For rat instillation, silica was first prepared in saline at a final concentration of 50 mg/mL after sterilized by autoclave (0.1Mpa, 120℃,
Characterization of silica particles
The silica particles used in this study were characterized as described previously(Zhu et al., 2016). SEM and TEM of silica particles exhibited a relatively irregular morphology and more obvious aggregation phenomena (Fig. 1A&B). The peaks of the silica particle size were distributed at 189.8 nm and 2647 nm, respectively (Fig. 1C). Despite the presence of many nanoscale silica, they are considered functionally micron-sized due to their aggregation in culture medium.
STS intervention reduces silica-induced pulmonary fibrosis in rats
We employed the rat model of
Discussion
Evidence accumulated over the past few decades has shown the importance of oxidative stress in organ fibrosis. However, numerous trials of anti-oxidants have failed to show improvement in patients with fibrotic diseases, and it remains unclear how ROS production can be targeted in such patients(Cheresh et al., 2013). Our previous studies showed that STS, the traditional Chinese medicine Salvia miltiorrhiza extract, could inhibit the activation of silica-induced lung fibroblasts by activating
Conclusions
Our study found that STS treatment of rats with silica-induced pulmonary fibrosis significantly reduced ROS and MDA production and collagen deposition, thereby antagonising pulmonary fibrosis induced by silica. The anti-fibrotic effects of STS may be related to the upregulation of Nrf2 expression and nuclear translocation and the subsequent increase in transcription of Trx and TrxR. Our results strongly support further studies of STS as a potential new agent for the treatment of silicosis.
CRediT authorship contribution statement
Zhonghui Zhu: Conceptualization, Methodology, Writing - review & editing. Qiuyue Li: Methodology, Software. Chunjie Xu: Methodology, Data Curation. Jing Zhao: Data Curation. Siling Li: Methodology, Data Curation. Yan Wang: Writing - review & editing. Lin Tian: Supervision.
Declaration of Competing Interest
The authors declare no potential conflicts of interest.
Acknowledgment and Funding Sources
This study was supported by the National Natural Science Foundation of China. (No. 81602832, 91643114 and 81973008); the Natural Science Foundation of Beijing (No. 7112015); the Specialized Research Fund for the Doctoral Program of Higher Education (No.20111107110016).
References (23)
- et al.
Oxidative stress and pulmonary fibrosis
Biochim. Biophys. Acta
(2013) - et al.
Role of interferon-gamma in the development of murine bronchus-associated lymphoid tissues induced by silica in vivo
Toxicol. Appl. Pharmacol.
(2002) - et al.
Thioredoxin and thioredoxin reductase: current research with special reference to human disease
Biochem. Biophys. Res. Commun.
(2010) - et al.
The thioredoxin antioxidant system
Free Radic. Biol. Med.
(2014) - et al.
Silica - A trace geogenic element with emerging nephrotoxic potential
Sci. Total Environ.
(2018) Thioredoxin and redox signaling: roles of the thioredoxin system in control of cell fate
Arch. Biochem. Biophys.
(2017)- et al.
Regulation of stress signaling pathways by protein lipoxidation
Redox Biol.
(2019) - et al.
MicroRNA-29b Mediates Lung Mesenchymal-Epithelial Transition and Prevents Lung Fibrosis in the Silicosis Model
Mol. Ther. Nucleic Acids
(2019) - et al.
Selenium supplementation of lung epithelial cells enhances nuclear factor E2-related factor 2 (Nrf2) activation following thioredoxin reductase inhibition
Redox Biol.
(2018) - et al.
Modulations of Keap1-Nrf2 signaling axis by TIIA ameliorated the oxidative stress-induced myocardial apoptosis
Free Radic. Biol. Med.
(2018)
Bone morphogenetic protein-7 inhibits silica-induced pulmonary fibrosis in rats
Toxicol. Lett.
Cited by (21)
TrxR/Trx inhibitor butaselen ameliorates pulmonary fibrosis by suppressing NF-κB/TGF-β1/Smads signaling
2023, Biomedicine and PharmacotherapyExpression of Thioredoxin System Protein Induced by Silica in Rat Lung Tissue
2022, Biomedical and Environmental SciencesNano-enabled delivery of EGCG ameliorates silica-induced pulmonary fibrosis in rats
2022, ToxicologyCitation Excerpt :The loss of body weight of all rats induced by silica was significantly evident as compared to the slightly increased in control group. A possible explanation, micron-sized silica had remarkable harmful and negative effects on appetite and weight in silicosis rats, while the control group appeared the opposite action (Karkale et al., 2018; Zhu et al., 2020). For the silica-induced groups, the weight of rats declined remarkably from days 1 to 7 (P < 0.01) followed by a gradual increase.
A comprehensive review of tanshinone IIA and its derivatives in fibrosis treatment
2021, Biomedicine and PharmacotherapyCitation Excerpt :In addition, it has been shown that Tan IIA could inhibit TGF-β1/Smad signaling pathway and prevent fibroblast proliferation in hypertrophic scar formation via long noncoding RNA (lncRNA)-human-specific regulatory loci/ Sorting nexin 9, indicating RNA interference is a promising strategy to reverse fibrosis [88]. STS, a derivative of Tan IIA, is widely used in the treatment of coronary heart disease [89]. Due to the similar molecular structure to Tan IIA, STS has been shown to exert potent anti-inflammatory, antioxidant, antifibrotic effects in various organs.
NBR1-p62-Nrf2 mediates the anti-pulmonary fibrosis effects of protodioscin
2024, Chinese Medicine (United Kingdom)A systematic review of the research progress of traditional Chinese medicine against pulmonary fibrosis: from a pharmacological perspective
2023, Chinese Medicine (United Kingdom)