scholarly journals Aesculetin Inhibits Pulmonary Fibrosis by Epithelial-to-mesenchymal Transition(EMT) in a Alveolar Epithelial Cell (P06-068-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Su Yeon Oh ◽  
Young-Hee Kang
Keyword(s):  
Pulmonary Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Alveolar Epithelial Cell ◽  
Smooth Muscle Actin ◽  
Pulmonary Inflammation ◽  
A549 Cells ◽  
Conditioned Media ◽  
Alveolar Cells ◽  
Mesenchymal Transition

Abstract Objectives Pulmonary fibrosis is a disease in which lung tissues become fibrous and causes severe respiratory disturbances. Various stimuli induce infiltration of macrophages to the respiratory tract. These macrophages secrete various cytokines leading to development of pulmonary fibrosis. Aesculetin, a major component of Sancho tree and Chicory, is known to have antioxidant and anti-inflammatory effects in the vascular and immune system. However, its effect on pulmonary fibrosis has been poorly understood. The current study investigated that aesculetin inhibited pulmonary fibrosis caused by infiltration of monocyte-derived macrophages. Methods To differentiate to monocyte-derived macrophages, THP-1 human mononuclear cell line was treated with 50 ng/ml phorbol myristate acetate (PMA) for 24 h. Culture conditioned media were harvested from macrophages cultured in the absence of PMA for 24 h. A549 human alveolar basal epithelial cells were cultured in the conditioned media for 24 h to induce alveolar fibrosis. Epithelial–mesenchymal transition (EMT)-associated fibrotic proteins were measured with Western blotting from A549 cell lysates. Results Aesculetin at the concentrations of 1–20 μM did not show any toxicity of A549 cells, evidence by MTT assay. When A549 cells were treated with conditioned media from monocyte-derived macrophages, the expression of mesenchymal fibrotic proteins of α-smooth muscle actin and fibronectin was highly enhanced. In contrast, ≥10 μM aesculetin inhibited the induction of these proteins of A549 cells. The expression of E-cadherin and Zonula occludens-1 was reduced in cells supplemented with conditioned media, while aesculetin promoted these epithelial phenotypic proteins in conditioned media-exposed alveolar cells. Conclusions These results demonstrate that aesculetin may ameliorate EMT-associated alveolar fibrosis caused by monocyte-derived macrophages infiltrated into the alveoli. Therefore, Aesculetin maybe a promising agent treating progressive pulmonary disorders owing to pulmonary inflammation. Funding Sources This work (Grants No. C0501612) was supported by project for Cooperative R&D between Industry, Academy, and Research Institute funded Korea Ministry of SMEs and Startups in 20.

scholarly journals Interleukin-22 Inhibits Bleomycin-Induced Pulmonary Fibrosis

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Minrui Liang ◽  
Jiucun Wang ◽  
Haiyan Chu ◽  
Xiaoxia Zhu ◽  
Hang He ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Alveolar Epithelial Cell ◽  
Smooth Muscle Actin ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Epithelial Cell Line ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial

Pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Recent insight has suggested that early injury/inflammation of alveolar epithelial cells could lead to dysregulation of tissue repair driven by multiple cytokines. Although dysregulation of interleukin- (IL-) 22 is involved in various pulmonary pathophysiological processes, the role of IL-22 in fibrotic lung diseases is still unclear and needs to be further addressed. Here we investigated the effect of IL-22 on alveolar epithelial cells in the bleomycin- (BLM-) induced pulmonary fibrosis. BLM-treated mice showed significantly decreased level of IL-22 in the lung. IL-22 producedγδT cells were also decreased significantly both in the tissues of lungs and spleens. Administration of recombinant human IL-22 to alveolar epithelial cell line A549 cells ameliorated epithelial to mesenchymal transition (EMT) and partially reversed the impaired cell viability induced by BLM. Furthermore, blockage of IL-22 deteriorated pulmonary fibrosis, with elevated EMT marker (α-smooth muscle actin (α-SMA)) and overactivated Smad2. Our results indicate that IL-22 may play a protective role in the development of BLM-induced pulmonary fibrosis and may suggest IL-22 as a novel immunotherapy tool in treating pulmonary fibrosis.

scholarly journals Aesculetin Attenuates Pulmonary Fibrosis Induced by Close Contact of Macrophages with Alveolar Epithelial Cells

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1531-1531
Author(s):  
Suyeon Oh ◽  
Young-Hee Kang
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
A549 Cells ◽  
Conditioned Media ◽  
Alveolar Epithelial Cells ◽  
Alveolar Cells ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Funding Sources ◽  
E Cadherin

Abstract Objectives Pulmonary fibrosis is a disease in which lung tissues become fibrous and causes severe respiratory disturbances. Various stimuli induce infiltration of macrophages to the respiratory tract. These macrophages secrete various inflammatory cytokines leading to development of pulmonary fibrosis via epithelial–mesenchymal transition (EMT) process. Aesculetin, a major component of Sancho tree and Chicory, is known to have antioxidant and anti-inflammatory effects in the vascular and immune system. Methods Human alveolar basal epithelial A549 cells were cultured in conditioned media of THP-1 monocyte-derived macrophages for 24 h. Aesculetin at the concentrations of 1–20 μM did not show cytotoxicity of A549 cells. Alveolar epithelial cells were incubated with interleukin (IL)-8. Western blotting examined EMT-associated fibrotic proteins from A549 cell lysates. Matrix metalloproteinase (MMP) activity was measured with gelatin zymography. In addition, inflammation- and fibrosis-related cytokines were measured by using ELISA kits. Results The epithelial markers of E-cadherin and ZO-1 were reduced in cells exposed to macrophage-conditioned media containing IL-8 and TNF-α. Macrophage-conditioned media enhanced expression of the mesenchymal fibrotic markers of α-smooth muscle actin (α-SMA), vimentin and fibronectin, and the fibrotic proteins of collagen I and collagen IV were enhanced. However, ≥10 μM aesculetin reciprocally manipulated the expression levels of these proteins of A549 cells. In addition, macrophage-conditioned media enhanced the expression and activity of MT1-MMP, MMP-2 and MMP-9. In contrast, the expression of tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 were reduced by exposure of alveolar cells to conditioned media. Proinflammatory and chemotactic IL-8 reduced E-cadherin and conversely enhanced N-cadherin and α-SMA in A549 cells, which was reciprocally modulated by ≥ 10 μM aesculetin. These results demonstrate that aesculetin may ameliorate EMT-associated pulmonary fibrosis caused by contact of blood-derived macrophages and alveolar cells. Conclusions Aesculetin maybe a promising agent treating progressive pulmonary disorders owing to macrophage-mediated inflammation. Funding Sources No funding sources to report.

scholarly journals Anti-Fibrotic Effects of Low Toxic Microcystin-RR on Bleomycin-Induced Pulmonary Fibrosis: A Comparison with Microcystin-LR

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Wang ◽  
Yan Ren ◽  
Xiufen Zheng ◽  
Jiaqi Kang ◽  
Zhenqian Huang ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Treatment Options ◽  
Pulmonary Inflammation ◽  
M2 Macrophages ◽  
Mesenchymal Transition ◽  
Matrix Deposition

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pulmonary disease characterized with radiographically evident pulmonary infiltrates and extracellular matrix deposition with limited treatment options. We previously described that microcystin-LR (MC-LR) reduces transforming growth factor (TGF)-β1/Smad signaling and ameliorates pulmonary fibrosis in bleomycin (BLM)-induced rat models. In the present study, we further demonstrate that microcystin-RR (MC-RR), an MC congener with lower toxicity than MC-LR, exerted an anti-fibrotic effect on BLM-induced pulmonary fibrosis rodent models and compared it with MC-LR. Our data show that MC-RR treatment attenuated BLM-associated pulmonary inflammation and collagen deposition in both therapeutic and preventive models. MC-RR reduced the expression of fibrotic markers, including vimentin, α-smooth muscle actin, collagen 1α1, and fibronectin, in rat pulmonary tissues. Furthermore, the core features of BLM-induced pulmonary fibrotic lesions were better alleviated by MC-RR than by MC-LR. MC-RR treatment substantially decreased the number of pulmonary M2 macrophages. In vitro, MC-RR attenuated the epithelial-mesenchymal transition and fibroblast-myofibroblast transition triggered by M2 macrophages. Therefore, we highlight MC-RR as a promising molecule for developing therapeutic and prophylactic strategies against IPF, a refractory lung disease.

MiRNA, a New Treatment Strategy for Pulmonary Fibrosis

2020 ◽  
Vol 21 ◽  
Author(s):  
Yanhong Liu ◽  
Hongguang Nie ◽  
Yan Ding ◽  
Yapeng Hou ◽  
Kejun Mao ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Alveolar Epithelial Cell ◽  
The Elderly ◽  
Matrix Remodeling ◽  
Mesenchymal Transition ◽  
Delay In Diagnosis ◽  
Alveolar Epithelial ◽  
Epithelial Cell Apoptosis ◽  
New Treatment

: Pulmonary fibrosis (PF) is the most common chronic, progressive interstitial lung disease, mainly occurring in the elderly, with a median survival of 2-4 years after diagnosis. Its high mortality rate attributes to the delay in diagnosis due to its generic symptoms, and more importantly, to the lack of effective treatments. MicroRNAs (miRNAs) are a class of small non-coding RNAs that involve in many essential cellular processes, including extracellular matrix remodeling, alveolar epithelial cell apoptosis, epithelial-mesenchymal transition, etc. We summarized the dysregulated miRNAs in TGF-β signaling pathway-mediated PF in recent years with dual effects, such as anti-fibrotic let-7 family and pro-fibrotic miR-21 members. Therefore, this review will set out the latest application of miRNAs to provide a new direction for PF treatment.

scholarly journals Network Pharmacology and Experimental Assessment to Explore the Pharmacological Mechanism of Qimai Feiluoping Decoction Against Pulmonary Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yingying Yang ◽  
Lu Ding ◽  
Tingting Bao ◽  
Yaxin Li ◽  
Jing Ma ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Clinical Symptoms ◽  
A549 Cells ◽  
Network Pharmacology ◽  
Active Components ◽  
Mesenchymal Transition ◽  
Pharmacological Mechanism ◽  
Ecm Degradation ◽  
Tgf Β1

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.

scholarly journals An Assessment of Epithelial and Mesenchymal Phenotypes in Experimental and Clinical Pulmonary Fibrosis

2012 ◽  
Vol 2012 ◽  
pp. 1-11
Author(s):  
Rebecca Dunmore ◽  
Alan M. Carruthers ◽  
Matthew J. Bell ◽  
Huilan Zhang ◽  
Cory M. Hogaboam ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
A549 Cells ◽  
Mesenchymal Cell ◽  
Experimental Models ◽  
Epithelial Injury ◽  
Mesenchymal Transition ◽  
Cell Markers ◽  
Apoptotic Marker ◽  
Lung Biopsies

Epithelial injury has been implicated as a driving factor for the pathogenesis of idiopathic pulmonary fibrosis (IPF). In this study we investigated changes in epithelial and mesenchymal markers in experimental models of fibrosis and associated this with IPF. TGFβ1 induced an epithelial to mesenchymal transition (EMT) phenotype in A549 cells and normal human bronchial epithelial cells, with A549 cells exhibiting a more profound transition to a mesenchymal phenotype. TGFβ1 overexpression in the lungs of mice resulted in an early increase in mesenchymal cell markers and apoptotic genes that preceded collagen deposition, suggesting an early epithelial injury triggers the downstream fibrotic response. In contrast, bleomycin had a gradual increase in mesenchymal cell marker and a decrease in E-cadherin expression that correlated with collagen protein deposition. Finally, we compared normal healthy lung tissue with surgical lung biopsies from IPF patients and observed alterations in epithelial and mesenchymal cell markers, as well as an increase in the apoptotic marker GSK3β. Interestingly, the mesenchymal changes were more profound in rapidly progressive patients in comparison to IPF patients with slowing progressing disease. In summary, this study provides evidence of alterations in epithelial and mesenchymal markers in experimental models of lung fibrosis and how these findings are relevant to clinical disease.

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

2020 ◽  
Vol 40 (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.

scholarly journals Arctigenin Suppressed Epithelial-Mesenchymal Transition Through Wnt3a/β-Catenin Pathway in PQ-Induced Pulmonary Fibrosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Fei Gao ◽  
Yun Zhang ◽  
Zhizhou Yang ◽  
Mengmeng Wang ◽  
Zhiyi Zhou ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Lung Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Underlying Mechanism ◽  
Alveolar Type ◽  
Mesenchymal Transition

Arctigenin (ATG), a major bioactive substance of Fructus Arctii, counters renal fibrosis; however, whether it protects against paraquat (PQ)-induced lung fibrosis remains unknown. The present study was to determine the effect of ATG on PQ-induced lung fibrosis in a mouse model and the underlying mechanism. Firstly, we found that ATG suppressed PQ-induced pulmonary fibrosis by blocking the epithelial-mesenchymal transition (EMT). ATG reduced the expressions of Vimentin and α-SMA (lung fibrosis markers) induced by PQ and restored the expressions of E-cadherin and Occludin (two epithelial markers) in vivo and in vitro. Besides, the Wnt3a/β-catenin signaling pathway was significantly activated in PQ induced pulmonary fibrosis. Further analysis showed that pretreatment of ATG profoundly abrogated PQ-induced EMT-like phenotypes and behaviors in A549 cells. The Wnt3a/β-catenin signaling pathway was repressed by ATG treatment. The overexpression of Wnt3a could weaken the therapeutic effect of ATG in A549 cells. These findings suggested that ATG could serve as a new therapeutic candidate to inhibit or even reverse EMT-like changes in alveolar type II cells during PQ-induced lung fibrosis, and unraveled that the Wnt3a/β-catenin pathway might be a mechanistic tool for ATG to control pulmonary fibrosis.

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.

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