Mechanistic insights into the treatment of pulmonary fibrosis with bioactive components from traditional chinese medicine via matrix stiffness-mediated EMT

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2024-11-17 DOI:10.1016/j.phymed.2024.156266

Kangchen Li , Han Liu , Mingyan Li , Meihao Sun , Xiling Peng , Yuanyuan Wu , Yange Tian , Xinguang Liu , Jiansheng Li

{"title":"Mechanistic insights into the treatment of pulmonary fibrosis with bioactive components from traditional chinese medicine via matrix stiffness-mediated EMT","authors":"Kangchen Li , Han Liu , Mingyan Li , Meihao Sun , Xiling Peng , Yuanyuan Wu , Yange Tian , Xinguang Liu , Jiansheng Li","doi":"10.1016/j.phymed.2024.156266","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. Our previous research has shown that the Jinshui Huanxian formula (JHF) is effective in treating IPF. However, the biomechanical mechanisms of its refined components, known as the effective-component compatibility of JHF II (ECC-JHF II), are not well understood.</div></div><div><h3>Purpose</h3><div>This study aims to explore how bioactive components from traditional Chinese medicine (TCM) impact the biomechanical progression of pulmonary fibrosis.</div></div><div><h3>Study design and methods</h3><div>A mouse model of pulmonary fibrosis was established by a single intratracheal instillation of bleomycin (Bleomycin). Pulmonary function, pathological changes, collagen deposition, lung tissue stiffness, and EMT markers were evaluated at the end of the study. Polyethylene glycol hydrogels with adjustable stiffness were used to mimic both normal and pathological lung conditions. The effects of ECC-JHF II on matrix stiffness-mediated EMT were assessed by quantitative real-time PCR, western blot, and immunofluorescence. The biomechanical mechanisms underlying ECC-JHF II on EMT and pulmonary fibrosis were verified both in vivo and in vitro.</div></div><div><h3>Results</h3><div>ECC-JHF II significantly improved bleomycin (Bleomycin)-induced pulmonary fibrosis in mice, manifested as increased tidal volume and 50 % tidal volume expiratory flow, reduced lung tissue stiffness, and decreased EMT markers. Histopathological analysis showed reduced inflammation, alveolar damage, and collagen deposition. In vitro, ECC-JHF II reversed the EMT phenotypic transition induced by substrate stiffness, demonstrated by the upregulation of E-cadherin, occludin, and zonula occluden-1, and the downregulation of N-cadherin, vimentin, caldesmon 1 and tropomyosin 1. Moreover, ECC-JHF II could inhibit integrin/ROCK/MRTF signaling in vitro and in vivo. Silencing integrin β1 or activating it with pyrintegrin further confirmed the role of integrin β1 in the mechanotransduction pathway and the efficacy of ECC-JHF II.</div></div><div><h3>Conclusion</h3><div>Taken together, the findings of this study indicate that ECC-JHF II exerts a therapeutic effect on pulmonary fibrosis through the attenuation of lung tissue stiffness and inhibition of EMT, potentially via the integrin/ROCK/MRTF signaling pathway.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"Article 156266"},"PeriodicalIF":6.7000,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Phytomedicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S094471132400922X","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. Our previous research has shown that the Jinshui Huanxian formula (JHF) is effective in treating IPF. However, the biomechanical mechanisms of its refined components, known as the effective-component compatibility of JHF II (ECC-JHF II), are not well understood.

Purpose

This study aims to explore how bioactive components from traditional Chinese medicine (TCM) impact the biomechanical progression of pulmonary fibrosis.

Study design and methods

A mouse model of pulmonary fibrosis was established by a single intratracheal instillation of bleomycin (Bleomycin). Pulmonary function, pathological changes, collagen deposition, lung tissue stiffness, and EMT markers were evaluated at the end of the study. Polyethylene glycol hydrogels with adjustable stiffness were used to mimic both normal and pathological lung conditions. The effects of ECC-JHF II on matrix stiffness-mediated EMT were assessed by quantitative real-time PCR, western blot, and immunofluorescence. The biomechanical mechanisms underlying ECC-JHF II on EMT and pulmonary fibrosis were verified both in vivo and in vitro.

Results

ECC-JHF II significantly improved bleomycin (Bleomycin)-induced pulmonary fibrosis in mice, manifested as increased tidal volume and 50 % tidal volume expiratory flow, reduced lung tissue stiffness, and decreased EMT markers. Histopathological analysis showed reduced inflammation, alveolar damage, and collagen deposition. In vitro, ECC-JHF II reversed the EMT phenotypic transition induced by substrate stiffness, demonstrated by the upregulation of E-cadherin, occludin, and zonula occluden-1, and the downregulation of N-cadherin, vimentin, caldesmon 1 and tropomyosin 1. Moreover, ECC-JHF II could inhibit integrin/ROCK/MRTF signaling in vitro and in vivo. Silencing integrin β1 or activating it with pyrintegrin further confirmed the role of integrin β1 in the mechanotransduction pathway and the efficacy of ECC-JHF II.

Conclusion

Taken together, the findings of this study indicate that ECC-JHF II exerts a therapeutic effect on pulmonary fibrosis through the attenuation of lung tissue stiffness and inhibition of EMT, potentially via the integrin/ROCK/MRTF signaling pathway.

Abstract Image

查看原文本刊更多论文

中药生物活性成分通过基质僵化介导的 EMT 治疗肺纤维化的机理研究

背景特发性肺纤维化（IPF）是一种进行性间质性肺病，治疗方法有限。我们之前的研究表明，金水合欢散（JHF）能有效治疗 IPF。本研究旨在探讨中药中的生物活性成分如何影响肺纤维化的生物力学进展。研究设计与方法通过气管内单次灌注博莱霉素（Bleomycin）建立肺纤维化小鼠模型。研究结束时对肺功能、病理变化、胶原沉积、肺组织硬度和 EMT 标记进行评估。使用硬度可调的聚乙二醇水凝胶来模拟正常和病理肺部情况。通过实时定量 PCR、Western 印迹和免疫荧光评估了 ECC-JHF II 对基质硬度介导的 EMT 的影响。结果ECC-JHF II显著改善了博莱霉素（Bleomycin）诱导的小鼠肺纤维化，表现为潮气量和50%潮气量呼气流量增加，肺组织僵硬度降低，EMT标记物减少。组织病理学分析表明，炎症、肺泡损伤和胶原沉积均有所减轻。在体外，ECC-JHF II 逆转了由基质僵化诱导的 EMT 表型转变，表现为 E-cadherin、occludin 和 zonula occluden-1 的上调，以及 N-cadherin、vimentin、caldesmon 1 和 tropomyosin 1 的下调。此外，ECC-JHF II 还能在体外和体内抑制整合素/ROCK/MRTF 信号转导。结论综上所述，本研究的结果表明，ECC-JHF II 可能通过整合素/ROCK/MRTF 信号通路，通过减轻肺组织僵硬度和抑制 EMT 对肺纤维化发挥治疗作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.