Effects of Nervilia fordii Extract on Pulmonary Fibrosis Through TGF-β/Smad Signaling Pathway.

Yufeng Yao,Yunxia Ma,Zenghui Lu,Yuanyuan Xie,Chaozhan Lin,Yue Yuan,Chenchen Zhu,Fangle Liu,Meiqi Wang

doi:10.3389/fphar.2021.659627

Yufeng Yao, Yunxia Ma + Show 7 more

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https://doi.org/10.3389/fphar.2021.659627

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease with a poor prognosis. The extract of Nervilia fordii (NFE) has shown remarkable benefit in the treatment of acute lung injury, lung cancer, and severe acute respiratory syndrome (SARS). However, the potential mechanism and efficacy of NFE in the treatment of IPF remain unknown. In this study, a systematic network pharmacology analysis was used to predict the mechanism and efficacy of NFE in the treatment of IPF, based on the major components of NFE elucidated by UPLC-TOF-MS/MS. The potential molecular interactions between the compounds and potential targets were predicted using molecular docking. In vivo, rats with pulmonary fibrosis induced by a single intratracheal injection of bleomycin (BLM) were orally administered NFE for 14 days. Lung index and biochemical levels were determined, and histopathological analysis using hematoxylin and eosin (H&E) and Masson staining was performed. The effects of NFE on fibroblast proliferation in Lipopolysaccharide (LPS) and TGF-β1-induced mouse 3T6 fibroblasts were evaluated in vitro. In total, 20 components were identified in NFE, and 102 potential targets for IPF treatment were predicted. These targets potentially participate in processes regulated by transmembrane receptor protein tyrosine kinase, ERBB2, and et al. Molecular docking results predicted high affinity interactions between three components (rhamnazin, rhamnetin, and rhamnocitrin) and the potential targets, suggesting that TGF-β is the most important potential target of NFE in the treatment of pulmonary fibrosis. NFE significantly decreased the lung index and alleviated BLM-induced pulmonary fibrosis in rats. Histopathological observation of lung tissues showed that NFE alleviated inflammation and collagen deposition in BLM-induced rats. NFE inhibited the migration of LPS- and TGF-β1-induced 3T6 fibroblasts, reduced the contents of hydroxyproline and collagen, and contributed to anti-inflammation and anti-oxidation. With the intervention of NFE, the protein and RNA expression of TGF-β1, a-SMA, Smad3/4, p-Smad3/4, CTGF, and p-ERK1/2 were significantly downregulated, while Smad7 and ERK1/2 were upregulated significantly in vivo and in vitro. These findings indicated that NFE may exert therapeutic effects on pulmonary fibrosis by alleviating inflammation, oxidation, and collagen deposition. The mechanism related to the inhibition of the TGF-β/Smad signaling pathway.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease characterized by a chronic inflammatory response, excessive proliferation of fibroblasts, aberrant deposition of extracellular matrix (ECM), and abnormal repair and remodeling of lung tissue (Wilson and Wynn, 2009; Sgalla et al, 2018)
To investigate whether the therapeutic efficacy of N. fordii extract (NFE) in the BLM-induced model was due to the reduction in the TGFβ/Smad pathway signaling in rats, we investigated the effect of NFE on the expression of TGF-β1, Smad3/4/7, and α-smooth muscle actin (α-SMA)
Pulmonary fibrosis is a fatal lung disease characterized by the accumulation of ECM as a result of lung remodeling

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease characterized by a chronic inflammatory response, excessive proliferation of fibroblasts, aberrant deposition of extracellular matrix (ECM), and abnormal repair and remodeling of lung tissue (Wilson and Wynn, 2009; Sgalla et al, 2018). Studies have shown that several factors, such as environmental pollution, smoking, bacterial, and viral infection, including SARS-CoV and MERS-CoV, can lead to severe lung inflammation, poor wound healing response, permanent organ damage, and fibrosis. Pirfenidone and nintedanib are two newly developed anti-pulmonary fibrosis drugs that significantly improve function and delay the progression of IPF (Brunnemer et al, 2018; Yoon et al, 2019; Chung et al, 2020). Owing to their high price and side effects, the use of these drugs is often limited in clinical settings. Because effective conventional drugs against IPF are limited, new therapeutic drugs and approaches are needed

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