scholarly journals Nanoapproaches to Modifying Epigenetics of Epithelial Mesenchymal Transition for Treatment of Pulmonary Fibrosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Melissa Skibba ◽  
Adam Drelich ◽  
Michael Poellmann ◽  
Seungpyo Hong ◽  
Allan R. Brasier
Keyword(s):  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Polymeric Nanoparticles ◽  
Pulmonary Delivery ◽  
High Morbidity ◽  
Airway Epithelial ◽  
Mesenchymal Transition ◽  
Rate Of Decline ◽  
Preclinical Work

Idiopathic Pulmonary Fibrosis (IPF) is a chronically progressive interstitial lung that affects over 3 M people worldwide and rising in incidence. With a median survival of 2–3 years, IPF is consequently associated with high morbidity, mortality, and healthcare burden. Although two antifibrotic therapies, pirfenidone and nintedanib, are approved for human use, these agents reduce the rate of decline of pulmonary function but are not curative and do not reverse established fibrosis. In this review, we discuss the prevailing epithelial injury hypothesis, wherein pathogenic airway epithelial cell-state changes known as Epithelial Mesenchymal Transition (EMT) promotes the expansion of myofibroblast populations. Myofibroblasts are principal components of extracellular matrix production that result in airspace loss and mortality. We review the epigenetic transition driving EMT, a process produced by changes in histone acetylation regulating mesenchymal gene expression programs. This mechanistic work has focused on the central role of bromodomain-containing protein 4 in mediating EMT and myofibroblast transition and initial preclinical work has provided evidence of efficacy. As nanomedicine presents a promising approach to enhancing the efficacy of such anti-IPF agents, we then focus on the state of nanomedicine formulations for inhalable delivery in the treatment of pulmonary diseases, including liposomes, polymeric nanoparticles (NPs), inorganic NPs, and exosomes. These nanoscale agents potentially provide unique properties to existing pulmonary therapeutics, including controlled release, reduced systemic toxicity, and combination delivery. NP-based approaches for pulmonary delivery thus offer substantial promise to modify epigenetic regulators of EMT and advance treatments for IPF.

The role of miR-29 in pulmonary fibrosis

2015 ◽  
Vol 93 (2) ◽  
pp. 109-118 ◽  
Author(s):  
Leah Cushing ◽  
Pingping Kuang ◽  
Jining Lü
Keyword(s):  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Pathological Condition ◽  
Lung Parenchyma ◽  
Interstitial Lung Diseases ◽  
Toxic Substances ◽  
Chronic Infections ◽  
Mesenchymal Transition

Pulmonary fibrosis is a pathological condition in which lungs become scarred due to the excess extracellular matrix (ECM) deposition and structural alterations in the interstitium of lung parenchyma. Many patients with interstitial lung diseases (ILDs) caused by long-term exposure to toxic substances, chronic infections, or autoimmune responses develop fibrosis. Etiologies for many ILDs are unknown, such as idiopathic pulmonary fibrosis (IPF), a devastating, relentless form of pulmonary fibrosis with a median survival of 2–3 years. Despite several decades of research, factors that initiate and sustain the fibrotic response in lungs remain unclear and there is no effective treatment to block progression of fibrosis. Here we summarize recent findings on the antifibrotic activity of miR-29, a small noncoding regulatory RNA, in the pathogenesis of fibrosis by regulating ECM production and deposition, and epithelial–mesenchymal transition (EMT). We also describe interactions of miR-29 with multiple profibrotic and inflammatory pathways. Finally, we review the antifibrotic activity of miR-29 in animal models of fibrosis and highlight miR-29 as a promising therapeutic reagent or target for the treatment of pulmonary fibrosis.

scholarly journals Downregulation of S100A2 alleviates pulmonary fibrosis through inhibiting wnt/β-catenin signaling pathway

2020 ◽  
Author(s):  
Guichuan Huang ◽  
Jing Zhang ◽  
Gang Qing ◽  
Daishun Liu ◽  
Xin Wang ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Western Blot ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Mesenchymal Transition ◽  
Qrt Pcr ◽  
Tgf Β1

Abstract Background：Pulmonary fibrosis (PF) is a progressive and lethal disease with poor prognosis. S100A2 plays an important role in the progression of cancer. However, the role of S100A2 in PF has not been reported yet. In this study, we explored the potential role of S100A2 in PF and its potential molecular mechanisms. Methods: First, we analyzed S100A2 expression of patients with PF by retrieving RNA-sequencing datasets from Gene Expression Omnibus (GEO) database. Next, we detected the expression of S100A2 in patients with PF using quantitative real time PCR (qRT-PCR). Then, S100A2 expression was determined with or without the treatment of transforming growth factor-β1 (TGF-β1) in A549 cells. Epithelial-mesenchymal transition (EMT) biomarkers, including E-cadherin，vimentin, and α smooth muscle actin (α-SMA), were identified using qRT-PCR and western blot. Finally, the relevant signalling pathway indicators were detected by western blot. Results: Increased expression of S100A2 was first observed in lung tissues of PF patients. Meanwhile, we found that downregulation of S100A2 inhibited the TGF-β1-induced EMT in A549 cells. Mechanically, TGF-β1 up-regulated β-catenin and phosphorylation of GSK-3β, which was blocked by silencing S100A2 in vitro. Conclusion: These findings demonstrate that downregulation of S100A2 alleviate pulmonary fibrosis via inhibiting EMT. S100A2 is a promising potential target for further understanding the mechanism and developing strategy for the treatment of PF and other EMT-associated disease.

scholarly journals Metformin Attenuates Silica-induced Pulmonary Fibrosis via AMPK Signaling

2021 ◽  
Author(s):  
Demin Cheng ◽  
Qi Xu ◽  
Yue Wang ◽  
Guanru Li ◽  
Wenqing Sun ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Pharmacological Action ◽  
Lung Epithelial Cells ◽  
Lung Fibroblasts ◽  
Mesenchymal Transition

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. SiO2-stimulated lung epithelial cells/macrophages and TGF-β-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 2mM to 10mM) 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.

scholarly journals Dual role of RACK1 in airway epithelial mesenchymal transition and apoptosis

2020 ◽  
Vol 24 (6) ◽  
pp. 3656-3668 ◽  
Author(s):  
Yue Pu ◽  
Yuan‐qi Liu ◽  
Yan Zhou ◽  
Yi‐fan Qi ◽  
Shi‐ping Liao ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Dual Role ◽  
Airway Epithelial ◽  
Mesenchymal Transition

scholarly journals Role of CXCL16 in BLM-induced epithelial–mesenchymal transition in human A549 cells

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zhenzhen Ma ◽  
Chunyan Ma ◽  
Qingfeng Zhang ◽  
Yang Bai ◽  
Kun Mu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Alveolar Type ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Tgf Β1

AbstractAlveolar epithelial cells play an essential role in the initiation and progression of pulmonary fibrosis, and the occurrence of epithelial–mesenchymal transition (EMT) may be the early events of pulmonary fibrosis. Recent studies have shown chemokines are involved in the complex process of EMT, and CXC chemokine ligand 16 (CXCL16) is also associated with many fibrosis-related diseases. However, whether CXCL16 is dysregulated in alveolar epithelial cells and the role of CXCL16 in modulating EMT in pulmonary fibrosis has not been reported. In this study, we found that CXCL16 and its receptor C-X-C motif chemokine receptor 6 (CXCR6) were upregulated in bleomycin induced EMT in human alveolar type II-like epithelial A549 cells. Synergistic effect of CXCL16 and bleomycin in promoting EMT occurrence, extracellular matrix (ECM) excretion, as well as the pro-inflammatory and pro-fibrotic cytokines productions in A549 cells were observed, and those biological functions were impaired by CXCL16 siRNA. We further confirmed that CXCL16 regulated EMT in A549 cells via the TGF-β1/Smad3 pathways. These results indicated that CXCL16 could promote pulmonary fibrosis by promoting the process of EMT via the TGF-β1/Smad3 signaling pathway.

Role of integrin-mediated TGFβ activation in the pathogenesis of pulmonary fibrosis

2009 ◽  
Vol 37 (4) ◽  
pp. 849-854 ◽  
Author(s):  
Amanda Goodwin ◽  
Gisli Jenkins
Keyword(s):  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β ◽  
Normal Lung ◽  
Membrane Repair ◽  
Mesenchymal Transition ◽  
Chronic Progressive Disease ◽  
Activation Pathways

IPF (idiopathic pulmonary fibrosis) is a chronic progressive disease of unknown aetiology without effective treatment. IPF is characterized by excessive collagen deposition within the lung. Recent evidence suggests that the lung epithelium plays a key role in driving the fibrotic response. The current paradigm suggests that, after epithelial injury, there is impaired epithelial proliferation and enhanced epithelial apoptosis. This in turn promotes lung fibrosis through impaired basement membrane repair and increased epithelial–mesenchymal transition. Furthermore, fibroblasts are recruited to the wounded area and adopt a myofibroblast phenotype, with the up-regulation of matrix-synthesizing genes and down-regulation of matrix-degradation genes. There is compelling evidence that the cytokine TGFβ (transforming growth factor β) plays a central role in this process. In normal lung, TGFβ is maintained in an inactive state that is tightly regulated temporally and spatially. One of the major TGFβ-activation pathways involves integrins, and the role of the αvβ6 integrin has been particularly well described in the pathogenesis of IPF. Owing to the pleiotropic nature of TGFβ, strategies that inhibit activation of TGFβ in a cell- or disease-specific manner are attractive for the treatment of chronic fibrotic lung conditions. Therefore the molecular pathways that lead to integrin-mediated TGFβ activation must be precisely defined to identify and fully exploit novel therapeutic targets that might ultimately improve the prognosis for patients with IPF.

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