Mechanism of Dandelion Sterol in Treating Pulmonary Fibrosis Through Transforming Growth Factor-β Signaling Pathway

2021 ◽  
Vol 11 (4) ◽  
pp. 612-618
Author(s):  
Qun Lv ◽  
Jianjun Wang ◽  
Zhaoyang Ruan
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Level ◽  
Lung Epithelial Cells ◽  
Migration And Invasion ◽  
Lung Epithelial ◽  
Tgf Β1

Background: The paper aimed to elucidate the molecular mechanism of Dandelion sterol in the treatment of pulmonary fibrosis, to study its effect on EMT of lung epithelial cells, and to find its target and downstream signaling pathways. Material and methods: The effects of Dandelion sterol on parathyroid (PQ)-induced EMT in lung epithelial cells were studied by immunofluorescence method. Immunohistochemistry and western-blot methods were used to verify that Dandelion sterol inhibited TGF-β1-induced EMT at the cellular level in animals, demonstrating that Dandelion sterol targets TGF-β1 to exert an anti-pulmonary fibrosis effect. Results: Dandelion sterol significantly inhibited PQ-induced migration and invasion of lung epithelial cells, and also inhibited the induced EMT. Dandelion sterol had a proper binding activity with the lung fibrosis-inducing factor TGF-β1. Dandelion sterol inhibited the TGF-β1-induced EMT process, and acted to treat pulmonary fibrosis by inhibiting the TGF-β1/Smad3 signaling pathway. Conclusion: Dandelion sterol can inhibit the pulmonary fibrosis by inhibiting the EMT process of lung epithelial cells through targeting the TGF- β1/Smad signaling pathway.

scholarly journals Dermatopontin interacts with transforming growth factor β and enhances its biological activity

1999 ◽  
Vol 337 (3) ◽  
pp. 537-541 ◽  
Author(s):  
Osamu OKAMOTO ◽  
Sakuhei FUJIWARA ◽  
Mayumi ABE ◽  
Yasufumi SATO
Keyword(s):  
Extracellular Matrix ◽  
Biological Activity ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Inhibitory Activity ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Tgf Β1

Dermatopontin, a recently found low-molecular-mass component of the extracellular matrix, was studied for its interaction with decorin and transforming growth factor β (TGF-β) and its influence on TGF-β bioactivity. Dermatopontin reacted with decorin with an apparent Kd of 100 nM in a solid-phase assay. Dermatopontin inhibited the formation of the decorin–TGF-β1 complex. Decorin also competed with dermatopontin for the binding of this cytokine. The dermatopontin–decorin complex bound 3-fold more TGF-β1 than did each component individually, and binding was inhibited more strongly by decorin preincubated with dermatopontin than by dermatopontin or decorin alone. Dermatopontin augmented the biological activity of TGF-β1, as analysed by the expression of luciferase in mink lung epithelial cells transfected with a plasminogen activator inhibitor–promoter–luciferase construct, although dermatopontin itself did not show apparent induction of luciferase. Dermatopontin showed weak inhibitory activity on the proliferation of mink lung epithelial cells, and it enhanced the growth-inhibitory activity of TGF-β on these cells. Thus dermatopontin increases the cellular response to TGF-β. These findings strongly suggest that dermatopontin modifies the behaviour of TGF-β through interaction with decorin in the microenvironment of the extracellular matrix in vivo.

scholarly journals Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Alison E. John ◽  
Rebecca H. Graves ◽  
K. Tao Pun ◽  
Giovanni Vitulli ◽  
Ellen J. Forty ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Small Molecule ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Lung Epithelial Cells ◽  
Tgfβ Signaling ◽  
Lung Epithelial ◽  
Translational Pharmacology ◽  
Αvβ6 Integrin

Abstract The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

scholarly journals Lung Fibrosis-associated Surfactant Protein A1 and C Variants Induce Latent Transforming Growth Factor β1 Secretion in Lung Epithelial Cells

2013 ◽  
Vol 288 (38) ◽  
pp. 27159-27171 ◽  
Author(s):  
Meenakshi Maitra ◽  
Moushumi Dey ◽  
Wen-Cheng Yuan ◽  
Peter W. Nathanielsz ◽  
Christine Kim Garcia
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Surfactant Protein ◽  
Transforming Growth Factor Β1 ◽  
Lung Epithelial Cells ◽  
Missense Mutations ◽  
Lung Epithelial ◽  
Tgf Β1

Missense mutations of surfactant proteins are recognized as important causes of inherited lung fibrosis. Here, we study rare and common surfactant protein (SP)-A1 and SP-C variants, either discovered in our familial pulmonary fibrosis cohort or described by others. We show that expression of two SP-A1 (R219W and R242*) and three SP-C (I73T, M71V, and L188Q) variant proteins lead to the secretion of the profibrotic latent transforming growth factor (TGF)-β1 in lung epithelial cell lines. The secreted TGF-β1 is capable of autocrine and paracrine signaling and is dependent upon expression of the latent TGF-β1 binding proteins. The dependence upon unfolded protein response (UPR) mediators for TGF-β1 induction differs for each variant. TGF-β1 secretion induced by the expression of the common SP-A1 R219W variant is nearly completely blocked by silencing the UPR transducers IRE-1α and ATF6. In contrast, the secretion of TGF-β1 induced by two rare SP-C mutant proteins (I73T and M71V), is largely unaffected by UPR silencing or by the addition of the small molecular chaperone 4-phenylbutyric acid, implicating a UPR-independent mechanism for these variants. Blocking TGF-β1 secretion reverses cell death of RLE-6TN cells expressing these SP-A1 and SP-C variants suggesting that anti-TGF-β therapeutics may be beneficial to this molecularly defined subgroup of pulmonary fibrosis patients.

scholarly journals GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis

2019 ◽  
Vol 317 (4) ◽  
pp. L510-L521 ◽  
Author(s):  
Yingze Zhang ◽  
Mao Jiang ◽  
Mehdi Nouraie ◽  
Mark G. Roth ◽  
Tracy Tabib ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Primary Source ◽  
Transforming Growth Factor Β ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Secreted Protein ◽  
Telomere Dysfunction

Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the interstitial lung diseases. Epithelial dysfunction is thought to play a prominent role in disease pathology, and we sought to characterize secreted signals that may contribute to disease pathology. Transcriptional profiling of senescent type II alveolar epithelial cells from mice with epithelial-specific telomere dysfunction identified the transforming growth factor-β family member, growth and differentiation factor 15 ( Gdf15), as the most significantly upregulated secreted protein. Gdf15 expression is induced in response to telomere dysfunction and bleomycin challenge in mice. Gdf15 mRNA is expressed by lung epithelial cells, and protein can be detected in peripheral blood and bronchoalveolar lavage following bleomycin challenge in mice. In patients with IPF, GDF15 mRNA expression in lung tissue is significantly increased and correlates with pulmonary function. Single-cell RNA sequencing of human lungs identifies epithelial cells as the primary source of GDF15, and circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and survival in multiple independent cohorts. Our findings suggest that GDF15 is an epithelial-derived secreted protein that may be a useful biomarker of epithelial stress and identifies IPF patients with poor outcomes.

scholarly journals miR-1343 attenuates pathways of fibrosis by targeting the TGF-β receptors

2016 ◽  
Vol 473 (3) ◽  
pp. 245-256 ◽  
Author(s):  
Lindsay R. Stolzenburg ◽  
Sarah Wachtel ◽  
Hong Dang ◽  
Ann Harris
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Lung Epithelial Cells ◽  
Lung Epithelial

A previously uncharacterized miRNA, miR-1343, was found to target and reduce the expression of transforming growth factor β (TGF-β) receptors 1 and 2. This led to significantly repressed TGF-β signalling in lung epithelial cells and fibroblasts and corresponding reductions in experimental markers of fibrosis.

scholarly journals Dexamethasone induces senescence of lung epithelial cells and augments TGF-β1-mediated production of the fibrosis mediator serpin E1 (plasminogen activator inhibitor-1)

2021 ◽  
Author(s):  
Francesca Louise Longhorne ◽  
Holly N Wilkinson ◽  
Matthew J Hardman ◽  
Simon Hart
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Cellular Senescence ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Lung Fibroblasts ◽  
Plasminogen Activator Inhibitor 1 ◽  
Lung Epithelial ◽  
Tgf Β1 ◽  
Pai 1

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, incurable scarring disease of the lungs with a prognosis worse than most cancers. Pathologically, IPF is characterised by upregulation of the pro-fibrotic cytokine transforming growth factor-β1 (TGF-β1), activation of fibroblasts, and deposition of collagen in the alveolar interstitium. Recent evidence has highlighted the role of senescent type 2 alveolar epithelial cells in the pathogenesis of IPF. In a clinical trial, a treatment regimen containing a corticosteroid drug accelerated pulmonary fibrosis leading to more hospitalizations and deaths, particularly in patients with telomere shortening which drives cellular senescence. Aim: To investigate the potential pro-fibrotic actions of corticosteroids on lung epithelial cells in vitro, including effects on cellular senescence and interactions with TGF-β1. Methods: The synthetic glucocorticoid dexamethasone (DEX) was incubated with A549 and BEAS-2B human lung epithelial cells in the presence or absence of TGF-β1. Cellular senescence was assessed by morphology, senescence-associated beta-galactosidase (SA β-Gal) expression, and qPCR for transcription of senescence-associated molecular markers. Conditioned media were screened for growth factors and cytokines and cultured with human lung fibroblasts. An IPF lung tissue RNA array dataset was re-analysed with a focus on senescence markers. Results: DEX induced senescence in lung epithelial cells associated with increased p21 (CDKN1A) expression independently of p16 (CDKN2A) or p53 (TP53). DEX amplified upregulation of the pro-fibrotic mediator serpin E1/plasminogen activator inhibitor-1 (PAI-1) in the presence of TGF-β1. The senescence-associated secretory phenotype from lung epithelial cells treated with DEX plus TGF-β1-treated contained increased concentrations of GM-CSF and IL-6 and when incubated with primary human lung fibroblasts there were trends to increased senescence and production of fibrosis markers. Upregulation of senescence markers was demonstrated by analysis of an IPF transcriptomic dataset. Discussion: DEX induces senescence in lung epithelial cell lines in vitro and interacts with TGF-β1 to amplify production of the pro-fibrotic mediator serpin E1 (PAI-1). This may be a mechanism by which corticosteroids promote pulmonary fibrosis in susceptible individuals. Serpin E1/PAI-1 is a potential druggable target in pulmonary fibrosis.

scholarly journals Metformin attenuates silica-induced pulmonary fibrosis via AMPK signaling

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Demin Cheng ◽  
Qi Xu ◽  
Yue Wang ◽  
Guanru Li ◽  
Wenqing Sun ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Lung Epithelial Cells ◽  
Lung Fibroblasts ◽  
Mesenchymal Transition ◽  
Tgf Β1

Abstract Background Silicosis is one of the most common occupational pulmonary fibrosis caused by respirable silica-based particle exposure, with no ideal drugs at present. Metformin, a commonly used biguanide antidiabetic agent, could activate AMP-activated protein kinase (AMPK) to exert its pharmacological action. Therefore, we sought to investigate the role of metformin in silica-induced lung fibrosis. Methods The anti-fibrotic role of metformin was assessed in 50 mg/kg silica-induced lung fibrosis model. Silicon dioxide (SiO2)-stimulated lung epithelial cells/macrophages and transforming growth factor-beta 1 (TGF-β1)-induced differentiated lung fibroblasts were used for in vitro models. Results At the concentration of 300 mg/kg in the mouse model, metformin significantly reduced lung inflammation and fibrosis in SiO2-instilled mice at the early and late fibrotic stages. Besides, metformin (range 2–10 mM) reversed SiO2-induced cell toxicity, oxidative stress, and epithelial-mesenchymal transition process in epithelial cells (A549 and HBE), inhibited inflammation response in macrophages (THP-1), and alleviated TGF-β1-stimulated fibroblast activation in lung fibroblasts (MRC-5) via an AMPK-dependent pathway. Conclusions In this study, we identified that metformin might be a potential drug for silicosis treatment.

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