Niclosamide Ethanolamine Salt Attenuated Idiopathic Pulmonary Fibrosis by Suppresses TGF-β1 Mediated Epithelial-Mesenchymal Transition

Pulmonary fibrosis (PF) is one of the pathologic changes in COVID-19 patients in convalescence, and it is also a potential long-term sequela in severe COVID-19 patients. Qimai Feiluoping decoction (QM) is a traditional Chinese medicine formula recommended in the Chinese national medical program for COVID-19 convalescent patients, and PF is one of its indications. Through clinical observation, QM was found to improve the clinical symptoms and pulmonary function and reduce the degree of PF of COVID-19 convalescent patients. To further explore the pharmacological mechanisms and possible active components of QM in anti-PF effect, UHPLC/Q-TOF-MS was used to analyze the composition of the QM extract and the active components that can be absorbed into the blood, leading to the identification of 56 chemical compounds and 10 active components. Then, network pharmacology was used to predict the potential mechanisms and targets of QM; it predicted that QM exerts its anti-PF effects via the regulation of the epithelial–mesenchymal transition (EMT), extracellular matrix (ECM) degradation, and TGF-β signaling pathway. Finally, TGF-β1–induced A549 cells were used to verify and explore the pharmacological effects of QM and found that QM could inhibit the proliferation of TGF-β1–induced A549 cells, attenuate EMT, and promote ECM degradation by inhibiting the TGF-β/Smad3 pathway.

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Epithelial–Mesenchymal Transition in the Pathogenesis of Idiopathic Pulmonary Fibrosis

Medicina ◽

10.3390/medicina55040083 ◽

2019 ◽

Vol 55 (4) ◽

pp. 83 ◽

Cited By ~ 23

Author(s):

Francesco Salton ◽

Maria Volpe ◽

Marco Confalonieri

Keyword(s):

Epithelial Cells ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Treatment Options ◽

Alveolar Epithelium ◽

Alveolar Epithelial Cells ◽

Mesenchymal Transition ◽

Alveolar Epithelial ◽

Serious Disease

Idiopathic pulmonary fibrosis (IPF) is a serious disease of the lung, which leads to extensive parenchymal scarring and death from respiratory failure. The most accepted hypothesis for IPF pathogenesis relies on the inability of the alveolar epithelium to regenerate after injury. Alveolar epithelial cells become apoptotic and rare, fibroblasts/myofibroblasts accumulate and extracellular matrix (ECM) is deposited in response to the aberrant activation of several pathways that are physiologically implicated in alveologenesis and repair but also favor the creation of excessive fibrosis via different mechanisms, including epithelial–mesenchymal transition (EMT). EMT is a pathophysiological process in which epithelial cells lose part of their characteristics and markers, while gaining mesenchymal ones. A role for EMT in the pathogenesis of IPF has been widely hypothesized and indirectly demonstrated; however, precise definition of its mechanisms and relevance has been hindered by the lack of a reliable animal model and needs further studies. The overall available evidence conceptualizes EMT as an alternative cell and tissue normal regeneration, which could open the way to novel diagnostic and prognostic biomarkers, as well as to more effective treatment options.

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Incomplete expression of epithelial–mesenchymal transition markers in idiopathic pulmonary fibrosis

Pathology - Research and Practice ◽

10.1016/j.prp.2011.06.006 ◽

2011 ◽

Vol 207 (9) ◽

pp. 559-567 ◽

Cited By ~ 28

Author(s):

Patrizia Morbini ◽

Simona Inghilleri ◽

Ilaria Campo ◽

Tiberio Oggionni ◽

Michele Zorzetto ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition

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Atractylodin Suppresses TGF-β-Mediated Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells and Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms222011152 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11152

Author(s):

Kai-Wei Chang ◽

Xiang Zhang ◽

Shih-Chao Lin ◽

Yu-Chao Lin ◽

Chia-Hsiang Li ◽

...

Keyword(s):

Epithelial Cells ◽

Pulmonary Fibrosis ◽

Lung Injury ◽

Epithelial Mesenchymal Transition ◽

A549 Cells ◽

Alveolar Epithelial Cells ◽

Collagen Deposition ◽

Mesenchymal Transition ◽

Alveolar Epithelial ◽

Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is characterized by fibrotic change in alveolar epithelial cells and leads to the irreversible deterioration of pulmonary function. Transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) in type 2 lung epithelial cells contributes to excessive collagen deposition and plays an important role in IPF. Atractylodin (ATL) is a kind of herbal medicine that has been proven to protect intestinal inflammation and attenuate acute lung injury. Our study aimed to determine whether EMT played a crucial role in the pathogenesis of pulmonary fibrosis and whether EMT can be utilized as a therapeutic target by ATL treatment to mitigate IPF. To address this topic, we took two steps to investigate: 1. Utilization of anin vitro EMT model by treating alveolar epithelial cells (A549 cells) with TGF-β1 followed by ATL treatment for elucidating the underlying pathways, including Smad2/3 hyperphosphorylation, mitogen-activated protein kinase (MAPK) pathway overexpression, Snail and Slug upregulation, and loss of E-cadherin. Utilization of an in vivo lung injury model by treating bleomycin on mice followed by ATL treatment to demonstrate the therapeutic effectiveness, such as, less collagen deposition and lower E-cadherin expression. In conclusion, ATL attenuates TGF-β1-induced EMT in A549 cells and bleomycin-induced pulmonary fibrosis in mice.

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Catalpol Protects Against Pulmonary Fibrosis Through Inhibiting TGF-β1/Smad3 and Wnt/β-Catenin Signaling Pathways

Frontiers in Pharmacology ◽

10.3389/fphar.2020.594139 ◽

2021 ◽

Vol 11 ◽

Author(s):

Fan Yang ◽

Zhen-feng Hou ◽

Hao-yue Zhu ◽

Xiao-xuan Chen ◽

Wan-yang Li ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Gene Expression Omnibus ◽

Matrix Remodeling ◽

Mesenchymal Transition ◽

Collagen Remodeling ◽

Gsk 3Β ◽

Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling; however, the molecular mechanisms underlying its occurrence and development are not yet fully understood. Despite it having a variety of beneficial pharmacological activities, the effects of catalpol (CAT), which is extracted from Rehmannia glutinosa, in IPF are not known. In this study, the differentially expressed genes, proteins, and pathways of IPF in the Gene Expression Omnibus database were analyzed, and CAT was molecularly docked with the corresponding key proteins to screen its pharmacological targets, which were then verified using an animal model. The results show that collagen metabolism imbalance, inflammatory response, and epithelial-mesenchymal transition (EMT) are the core processes in IPF, and the TGF-β1/Smad3 and Wnt/β-catenin pathways are the key signaling pathways for the development of pulmonary fibrosis. Our results also suggest that CAT binds to TGF-βR1, Smad3, Wnt3a, and GSK-3β through hydrogen bonds, van der Waals bonds, and other interactions to downregulate the expression and phosphorylation of Smad3, Wnt3a, GSK-3β, and β-catenin, inhibit the expression of cytokines, and reduce the degree of oxidative stress in lung tissue. Furthermore, CAT can inhibit the EMT process and collagen remodeling by downregulating fibrotic biomarkers and promoting the expression of epithelial cadherin. This study elucidates several key processes and signaling pathways involved in the development of IPF, and suggests the potential value of CAT in the treatment of IPF.

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Submicron emulsion of cinnamaldehyde ameliorates bleomycin-induced idiopathic pulmonary fibrosis via inhibition of inflammation, oxidative stress and epithelial-mesenchymal transition

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2018.03.145 ◽

2018 ◽

Vol 102 ◽

pp. 765-771 ◽

Cited By ~ 7

Author(s):

Li Yan ◽

Fan Song ◽

Hua Li ◽

Yao Li ◽

Jie Li ◽

...

Keyword(s):

Oxidative Stress ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Submicron Emulsion

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Bleomycin induces epithelial-to-mesenchymal transition via bFGF/PI3K/ESRP1 signaling in pulmonary fibrosis

Bioscience Reports ◽

10.1042/bsr20190756 ◽

2020 ◽

Vol 40 (1) ◽

Cited By ~ 1

Author(s):

Chang-Mei Weng ◽

Qing Li ◽

Kui-Jun Chen ◽

Cheng-Xiong Xu ◽

Meng-Sheng Deng ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Regulatory Protein ◽

A549 Cells ◽

Akt Signaling ◽

High Rate ◽

Akt Inhibitor ◽

Mesenchymal Transition ◽

Tgf Β1

Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal and chronic disease with a high rate of infection and mortality; however, its etiology and pathogenesis remain unclear. Studies have revealed that epithelial–mesenchymal transition (EMT) is a crucial cellular event in IPF. Here, we identified that the pulmonary fibrosis inducer bleomycin simultaneously increased the expression of bFGF and TGF-β1 and inhibited epithelial-specific regulatory protein (ESRP1) expression in vivo and in vitro. In addition, in vitro experiments showed that bFGF and TGF-β1 down-regulated the expression of ESRP1 and that silencing ESRP1 promoted EMT in A549 cells. Notably, we determined that bFGF activates PI3K/Akt signaling, and treatment with the PI3K/Akt inhibitor LY294002 inhibited bleomycin-induced cell morphology changes and EMT. In addition, the effects of LY294002 on bleomycin-induced EMT were inhibited by ESRP1 silencing in A549 cells. Taken together, these findings suggest that bleomycin induced EMT through down-regulating ESRP1 by simultaneously increasing bFGF and TGF-β1 in pulmonary fibrosis. Additionally, our findings indicated that bFGF inhibits ESRP1 by activating PI3K/Akt signaling.

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