scholarly journals Epithelial–Mesenchymal Transition in the Pathogenesis of Idiopathic Pulmonary Fibrosis

Medicina ◽  
2019 ◽  
Vol 55 (4) ◽  
pp. 83 ◽  
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.

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

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.

scholarly journals YY1 mediates TGF-β1-induced EMT and pro-fibrogenesis in alveolar epithelial cells

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Chuyi Zhang ◽  
Xiaoping Zhu ◽  
Yifei Hua ◽  
Qian Zhao ◽  
Kaijing Wang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Lung Damage ◽  
Type Ii ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial

Abstract Pulmonary fibrosis is a chronic, progressive lung disease associated with lung damage and scarring. The pathological mechanism causing pulmonary fibrosis remains unknown. Emerging evidence suggests prominent roles of epithelial–mesenchymal transition (EMT) of alveolar epithelial cells (AECs) in myofibroblast formation and progressive pulmonary fibrosis. Our previous work has demonstrated the regulation of YY1 in idiopathic pulmonary fibrosis and pathogenesis of fibroid lung. However, the specific function of YY1 in AECs during the pathogenesis of pulmonary fibrosis is yet to be determined. Herein, we found the higher level of YY1 in primary fibroblasts than that in primary epithelial cells from the lung of mouse. A549 and BEAS-2B cells, serving as models for type II alveolar pulmonary epithelium in vitro, were used to determine the function of YY1 during EMT of AECs. TGF-β-induced activation of the pro-fibrotic program was applied to determine the role YY1 may play in pro-fibrogenesis of type II alveolar epithelial cells. Upregulation of YY1 was associated with EMT and pro-fibrotic phenotype induced by TGF-β treatment. Targeted knockdown of YY1 abrogated the EMT induction by TGF-β treatment. Enforced expression of YY1 can partly mimic the TGF-β-induced pro-fibrotic change in either A549 cell line or primary alveolar epithelial cells, indicating the induction of YY1 expression may mediate the TGF-β-induced EMT and pro-fibrosis. In addition, the translocation of NF-κB p65 from the cytoplasm to the nucleus was demonstrated in A549 cells after TGF-β treatment and/or YY1 overexpression, suggesting that NF-κB-YY1 signaling pathway regulates pulmonary fibrotic progression in lung epithelial cells. These findings will shed light on the better understanding of mechanisms regulating pro-fibrogenesis in AECs and pathogenesis of lung fibrosis.

scholarly journals Therapeutic Potential of Exosomes in Pulmonary Fibrosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Linshen Xie ◽  
Ye Zeng
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Alveolar Epithelial Cells ◽  
Type Ii ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Key Factor ◽  
Marrow Mesenchymal Stem Cells

Pulmonary fibrosis is closely associated with the recruitment of fibroblasts from capillary vessels with damaged endothelial cells, the epithelial mesenchymal transition (EMT) of type II alveolar epithelial cells, and the transformation of fibroblasts to myofibroblasts. Recent studies suggest that EMT is a key factor in the pathogenesis of pulmonary fibrosis, as the disruption of EMT-related effector molecules can inhibit the occurrence and development of PF. With the numerous advancements made in molecular biology in recent years, researchers have discovered that exosomes and their cargos, such as miRNAs, lncRNAs, and proteins, can promote or inhibit the EMT, modulate the transformation of fibroblasts into myofibroblasts, contribute to the proliferation of fibroblasts and promote immunoregulatory and mitochondrial damage during pulmonary fibrosis. Exosomes are key factors regulating the differentiation of bone marrow mesenchymal stem cells (BMSCs) into myofibroblasts. Interestingly, exosomes derived from BMSCs under pathological and physiological conditions may promote or inhibit the EMT of type II alveolar epithelial cells and the transformation of fibroblasts into myofibroblasts to regulate pulmonary fibrosis. Thus, exosomes may become a new direction in the study of drugs for the treatment of pulmonary fibrosis.

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.

Dasatinib Suppresses TGFβ-Mediated Epithelial–Mesenchymal Transition in Alveolar Epithelial Cells and Inhibits Pulmonary Fibrosis

Lung ◽  
2018 ◽  
Vol 196 (5) ◽  
pp. 531-541 ◽  
Author(s):  
Ryota Kanemaru ◽  
Fumiyuki Takahashi ◽  
Motoyasu Kato ◽  
Yoichiro Mitsuishi ◽  
Ken Tajima ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Alveolar Epithelial Cells ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial

scholarly journals Hispidin attenuates bleomycin-induced idiopathic pulmonary fibrosis via an anti-oxidative effect in A549 cells

2021 ◽  
Vol 64 (1) ◽  
Author(s):  
Chen-Xi Ren ◽  
Xin Jin ◽  
Dan-Ping Xie ◽  
Xiao-Yu Guo ◽  
Li-Yun Yu ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Interstitial Fibrosis ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Oxidative Effects

AbstractIdiopathic pulmonary fibrosis (IPF) is a serious and irreversible chronic lung disease. Bleomycin (BLM) is an anticancer drug, which can cause severe lung toxicity. The main target of oxidative stress-induced lung injury is alveolar epithelial cells, which lead to interstitial fibrosis. The present study investigated whether hispidin (HP), which has excellent antioxidant activity, attenuates bleomycin-induced pulmonary fibrosis via anti-oxidative effects in A549 cells. We found that hispidin reduced bleomycin-induced fibrosis of A549 cells by reducing reactive oxygen species (ROS) levels and inhibiting epithelial-mesenchymal transition. Taken together, our data suggest that hispidin has therapeutic potential in preventing bleomycin-induced pulmonary fibrosis.

scholarly journals IL-25/IL-33/TSLP contributes to idiopathic pulmonary fibrosis: Do alveolar epithelial cells and (myo)fibroblasts matter?

2020 ◽  
Vol 245 (10) ◽  
pp. 897-901
Author(s):  
Xuefeng Xu ◽  
Jinglan Zhang ◽  
Huaping Dai
Keyword(s):  
Epithelial Cells ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Alveolar Epithelium ◽  
Alveolar Epithelial Cells ◽  
Dependent Manner ◽  
Treatment Target ◽  
Phenotypic Changes ◽  
Alveolar Epithelial ◽  
Fibrotic Process

Idiopathic pulmonary fibrosis is a relentless fibrotic disease with largely unknown etiologies. Currently, the crosstalk between alveolar epithelial cells and lung-resident mesenchymal cells (especially [myo]fibroblasts) is considered to be the central pathogenesis to initiate and propagate the fibrotic process. Unfortunately, the master switch hidden in the profibrotic milieu that mediates pathogenic epithelial-mesenchymal interactions is still not well elucidated. Thus, the definite treatment target that can block and cure idiopathic pulmonary fibrosis is now lacking. Based on the previous studies, we proposed the notion that epithelium-derived triple type 2 cytokines, i.e. interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) are important pro-fibrotic mediators in idiopathic pulmonary fibrosis via two possible mechanisms: (1) paracrine pathway: directly acting on (myo)fibroblast. There may exist a structural and functional axis of (IL-25/IL-33/TSLP)+alveolar epithelial cells-(IL-25R/IL-33R/TSLPR)+ (myo)fibroblasts in fibroblastic foci of idiopathic pulmonary fibrosis patients. The crosstalk between alveolar epithelium and the adjacent mesenchymal compartment is well established by the binding of IL-25/IL-33/TSLP expressed on alveolar epithelial cells with their corresponding receptors (i.e. IL-17BR/sT2L/TSLPR) expressed on (myo)fibroblasts; (2) autocrine pathway: directly acting on alveolar epithelial cells. Alveolar epithelial cells may act as both cellular sources and targets of IL-25/IL-33/TSLP. Autocrine IL-25/IL-33/TSLP causes salient injury and phenotypic changes of alveolar epithelial cells. Thus, epithelium-derived IL-25/IL-33/TSLP may be the novel promising treatment target for the cure of idiopathic pulmonary fibrosis. Impact statement We suggest a novel modality in terms of IL-25/IL-33/TSLP’s pro-fibrotic role in IPF. First, IL-25/IL-33/TSLP fully activates (myo)fibroblasts in fibroblastic foci (FF) in a paracrine-dependent manner. (IL-25/IL-33/TSLP)+alveolar epithelial cells-(IL-25R/IL-33R/TSLPR)+ (myo)fibroblasts axis may contribute greatly to the abnormal epithelial-mesenchymal crosstalk and lung fibrosis. Second, IL-25/IL-33/TSLP causes significant injury and phenotypic changes of alveolar epithelial cells in an autocrine-dependent manner. By acting directly on the two most important cells in the fibrotic process, i.e. alveolar epithelial cells and (myo)fibroblasts, we support the notion that biological therapies targeting IL-25/IL-33/TSLP will shed new light on the cure of IPF patients.

Induction of epithelial-mesenchymal transition by flagellin in cultured lung epithelial cells

2012 ◽  
Vol 303 (12) ◽  
pp. L1057-L1069 ◽  
Author(s):  
Yutaka Kondo ◽  
Sayomi Higa-Nakamine ◽  
Nobuhiro Noguchi ◽  
Noriko Maeda ◽  
Seikichi Toku ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Map Kinase ◽  
Epithelial Mesenchymal Transition ◽  
P38 Map Kinase ◽  
Alveolar Epithelial Cells ◽  
Simultaneous Treatment ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial

Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and activates host inflammatory responses, mainly through activation of the NF-κB pathway. Although pulmonary fibrosis occurs in some cases of lung infection by flagellated bacteria, the pathological roles of TLR5 stimulation in pulmonary fibrosis have yet to be elucidated. In the present study, we first confirmed that flagellin activated the NF-κB pathway in cultured A549 alveolar epithelial cells. Next, we examined the types of genes whose expression was modulated by flagellin in the cells. Microarray analysis of gene expression indicated that flagellin induced a change in gene expression that had a similar trend to transforming growth factor-β1 (TGF-β1), a key factor in the induction of epithelial-mesenchymal transition (EMT). Biochemical analysis revealed that TGF-β1 and flagellin increased the level of fibronectin protein, while they reduced the level of E-cadherin protein after 30 h of treatment. Interestingly, simultaneous treatment with TGF-β1 and flagellin significantly augmented these EMT-related changes. Flagellin strongly activated p38 MAP kinase, and the activation was sustained for longer than 30 h. SB203580, an inhibitor of p38 MAP kinase, inhibited the upregulation of fibronectin by both flagellin and TGF-β1. Simultaneous treatment with TGF-β1 and flagellin augmented the activation of p38 MAP kinase by TGF-β1 or flagellin alone. These results strongly suggest that flagellin cooperates with TGF-β1 in the induction of EMT in alveolar epithelial cells.

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