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.

Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism

1998 ◽  
Vol 275 (5) ◽  
pp. L1013-L1017 ◽  
Author(s):  
Bruce D. Uhal ◽  
Claudia Gidea ◽  
Raed Bargout ◽  
Antonio Bifero ◽  
Olivia Ibarra-Sunga ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Dna Fragmentation ◽  
Cell Apoptosis ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Epithelial Cell Apoptosis

The angiotensin-converting enzyme inhibitor captopril has been shown to inhibit fibrogenesis in the lung, but the mechanisms underlying this action are unclear. Apoptosis of lung epithelial cells is believed to be involved in the pathogenesis of pulmonary fibrosis. For these reasons, we studied the effect of captopril on Fas-induced apoptosis in a human lung epithelial cell line. Monoclonal antibodies that activate the Fas receptor induced epithelial cell apoptosis as detected by chromatin condensation, nuclear fragmentation, DNA fragmentation, and increased activities of caspase-1 and -3. Apoptosis was not induced by isotype-matched nonimmune mouse immunoglobulins or nonactivating anti-Fas monoclonal antibodies. When applied simultaneously with anti-Fas antibodies, 50 ng/ml of captopril completely abrogated apoptotic indexes based on morphology, DNA fragmentation, and inducible caspase-1 activity and significantly decreased the inducible activity of caspase-3. Inhibition of apoptosis by captopril was concentration dependent, with an IC50 of 70 pg/ml. These data suggest that the inhibitory actions of captopril on pulmonary fibrosis may be related to prevention of lung epithelial cell apoptosis.

scholarly journals Epithelial contribution to the profibrotic stiff microenvironment and myofibroblast population in lung fibrosis

2017 ◽  
Vol 28 (26) ◽  
pp. 3741-3755 ◽  
Author(s):  
Marta Gabasa ◽  
Paula Duch ◽  
Ignasi Jorba ◽  
Alícia Giménez ◽  
Roberto Lugo ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Lung Epithelial Cells ◽  
Lung Fibroblasts ◽  
Mesenchymal Transition ◽  
Collagen Expression ◽  
Fibrillar Collagens ◽  
Lung Epithelial ◽  
Fibrotic Disorder ◽  
Tgf Β1

The contribution of epithelial-to-mesenchymal transition (EMT) to the profibrotic stiff microenvironment and myofibroblast accumulation in pulmonary fibrosis remains unclear. We examined EMT-competent lung epithelial cells and lung fibroblasts from control (fibrosis-free) donors or patients with idiopathic pulmonary fibrosis (IPF), which is a very aggressive fibrotic disorder. Cells were cultured on profibrotic conditions including stiff substrata and TGF-β1, and analyzed in terms of morphology, stiffness, and expression of EMT/myofibroblast markers and fibrillar collagens. All fibroblasts acquired a robust myofibroblast phenotype on TGF-β1 stimulation. Yet IPF myofibroblasts exhibited higher stiffness and expression of fibrillar collagens than control fibroblasts, concomitantly with enhanced FAKY397 activity. FAK inhibition was sufficient to decrease fibroblast stiffness and collagen expression, supporting that FAKY397 hyperactivation may underlie the aberrant mechanobiology of IPF fibroblasts. In contrast, cells undergoing EMT failed to reach the values exhibited by IPF myofibroblasts in all parameters examined. Likewise, EMT could be distinguished from nonactivated control fibroblasts, suggesting that EMT does not elicit myofibroblast precursors either. Our data suggest that EMT does not contribute directly to the myofibroblast population, and may contribute to the stiff fibrotic microenvironment through their own stiffness but not their collagen expression. Our results also support that targeting FAKY397 may rescue normal mechanobiology in IPF.

The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability

2008 ◽  
Vol 295 (6) ◽  
pp. L967-L975 ◽  
Author(s):  
Sreerama Shetty ◽  
Joseph Padijnayayveetil ◽  
Torry Tucker ◽  
Dorota Stankowska ◽  
Steven Idell
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Plasminogen Activator ◽  
Mrna Stability ◽  
Fibrinolytic System ◽  
Lung Epithelial Cells ◽  
Lung Epithelial Cell ◽  
Plasminogen Activator Inhibitor 1 ◽  
Lung Epithelial ◽  
Pai 1

The urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) are key components of the fibrinolytic system and are expressed by lung epithelial cells. uPA, uPAR, and PAI-1 have been strongly implicated in the pathogenesis of acute lung injury (ALI) and pulmonary fibrosis. Recently, it has become clear that regulation of uPA, uPAR, and PAI-1 occurs at the posttranscriptional level of mRNA stability in lung epithelial cells. uPA further mediates its own expression in these cells as well as that of uPAR and PAI-1 through induction of changes in mRNA stability. In addition, uPA-mediated signaling controls the expression of the tumor suppressor protein p53 in lung epithelial cells at the posttranslational level. p53 has recently been shown to be a trans-acting uPA, uPAR, and PAI-1 mRNA-binding protein that regulates the stability of these mRNAs. It is now clear that signaling initiated by uPA mediates dose-dependent regulation of lung epithelial cell apoptosis and likewise involves changes in p53, uPA, uPAR, and PAI-1 expression. These findings demonstrate that the uPA-uPAR-PAI-1 system of lung epithelial cells mediates a broad repertoire of responses that encompass but extend well beyond traditional fibrinolysis, involve newly recognized interactions with p53 that influence the viability of the lung epithelium, and are thereby implicated in the pathogenesis of ALI and its repair.

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 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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