Sparganii Rhizoma alleviates pulmonary fibrosis by inhibiting fibroblasts differentiation and epithelial-mesenchymal transition mediated by TGF-β1/ Smad2/3 pathway

Pulmonary fibrosis (PF) is a fatal and irreversible disease of the respiratory system. It is an end-stage pathological change of the lung characterized by abnormal wound healing, myofibroblasts proliferation, and deposition of extracellular matrix, which eventually leads to respiratory failure and death (Wu et al., 2021; Yu and Tang, 2022). Among them, idiopathic pulmonary fibrosis is a particularly severe sort with an increasing incidence year by year and poor prognosis, and the median survival time of IPF patients is 3–5 years (Yanagihara et al., 2020). Risk factors for PF include genetics, autoimmune diseases, environmental factors, viral infections, drug reactions, etc., and are also related to age and gender (Mathai and Schwartz, 2019). There is no effective treatment except for lung transplantation (Ye and Hu, 2021). The commonly used anti-PF drugs, such as pirfenidone and nintedanib, can only slightly slow down the progression of the disease, but can not reverse it, and most patients who take them for a long time will have adverse reactions and significant withdrawal symptoms (Ghumman et al., 2021; Spagnolo et al., 2021; Zhang et al., 2021). Development of effective therapeutic drugs to attenuate PF cannot be neglected any longer.

PF is classified as Feibi and Feiwei in Chinese medicine and is often treated clinically by tonifying the lung, activating blood circulation, and eliminating blood stasis (Huang and Gong, 2016; Li et al., 2021). Sparganii Rhizoma (SR) was first recorded in Ben Cao Shi Yi, which was written by Chen Cangqi during the Tang Dynasty. SR is derived from the rhizome of Sparganium stoloniferum Buch.-Ham. (Sparganiaceae) (Tan et al., 2018) and has the effects of activating blood circulation and eliminating blood stasis, which is frequently used in the clinical treatment of pulmonary fibrosis with traditional Chinese medicine (Ma et al., 2020). Compared with the acetylcysteine treatment group, SR treatment could relieve clinical symptoms, improve lung function in patients with IPF (HE et al., 2019; Xi and Qin, 2018). Research has proved SR treatment could decrease the expression of collagen in rats with pulmonary fibrosis, reduce the degree of lung tissue lesions, and thus alleviate PF (Ren et al., 2020; Wang et al., 2011).

The pathogenesis of pulmonary fibrosis is complicated. It has been widely confirmed that fibroblasts proliferation and differentiation into myofibroblasts and epithelial-mesenchymal transformation are closely related to pulmonary fibrosis (Meyer, 2017; Richeldi et al., 2017; Sun et al., 2020). Myofibroblasts are a major source of large extracellular matrix deposition and can express the metalloproteinase inhibitor TIMP to inhibit extracellular matrix degradation, resulting in reduced gas exchange and decreased lung function (Craig et al., 2015). EMT means epithelial cells lost polarity and adhesion ability, and migration and invasion ability were enhanced (Salton et al., 2019). TGF-β1 is considered to be a vital regulatory factor in the development of PF, which can stimulate fibroblasts differentiation and promote the EMT process (Ong et al., 2021).

Studies have shown SR may improve uterine leiomyoma through regulating the TGF-β/Smad signaling pathway to reduce extracellular matrix deposition (Yu et al., 2019). SR drug-containing serum can inhibit the TGF-β1-induced EMT process to against triple-negative breast cancer (Yin et al., 2018). Based on this, we used SR to treat pulmonary fibrosis and found that SR effectively suppressed BLM-induced PF in mice. SR has been shown to inhibit fibroblasts differentiation and the EMT to achieve therapeutic effects in pulmonary fibrosis. In addition, we realized SR might play an anti-PF role through TGF-β1/Smad2/3 pathway.

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