scholarly journals Neutrophil Extracellular Traps Induce the Epithelial-Mesenchymal Transition: Implications in Post-COVID-19 Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura Pandolfi ◽  
Sara Bozzini ◽  
Vanessa Frangipane ◽  
Elena Percivalle ◽  
Ada De Luigi ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Tissue Injury ◽  
Lavage Fluid ◽  
Neutrophil Extracellular Traps ◽  
Lung Epithelial Cells ◽  
High Concentration ◽  
Mesenchymal Transition ◽  
Extracellular Traps ◽  
Epithelial Marker

The release of neutrophil extracellular traps (NETs), a process termed NETosis, avoids pathogen spread but may cause tissue injury. NETs have been found in severe COVID-19 patients, but their role in disease development is still unknown. The aim of this study is to assess the capacity of NETs to drive epithelial-mesenchymal transition (EMT) of lung epithelial cells and to analyze the involvement of NETs in COVID-19. Bronchoalveolar lavage fluid of severe COVID-19 patients showed high concentration of NETs that correlates with neutrophils count; moreover, the analysis of lung tissues of COVID-19 deceased patients showed a subset of alveolar reactive pneumocytes with a co-expression of epithelial marker and a mesenchymal marker, confirming the induction of EMT mechanism after severe SARS-CoV2 infection. By airway in vitro models, cultivating A549 or 16HBE at air-liquid interface, adding alveolar macrophages (AM), neutrophils and SARS-CoV2, we demonstrated that to trigger a complete EMT expression pattern are necessary the induction of NETosis by SARS-CoV2 and the secretion of AM factors (TGF-β, IL8 and IL1β). All our results highlight the possible mechanism that can induce lung fibrosis after SARS-CoV2 infection.

scholarly journals Neutrophil extracellular traps induce the epithelial-mesenchymal transition: implications in post-COVID-19 fibrosis

2020 ◽  
Author(s):  
Laura Pandolfi ◽  
Sara Bozzini ◽  
Vanessa Frangipane ◽  
Elena Percivalle ◽  
Ada De Luigi ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Tissue Injury ◽  
Neutrophil Extracellular Traps ◽  
Lung Epithelial Cells ◽  
Epithelial Cell Line ◽  
High Concentration ◽  
Mesenchymal Transition ◽  
Extracellular Traps ◽  
Lung Epithelial

AbstractThe release of neutrophil extracellular traps (NETs), a process termed NETosis, avoids pathogen spread but may cause tissue injury. NETs have been found in severe COVID-19 patients, but their role in disease development is still unknown. The aim of this study is to assess the capacity of NETs to drive epithelial-mesenchymal transition (EMT) of lung epithelial cells and to analyze the involvement of NETs in COVID-19.Neutrophils activated with PMA (PMA-Neu), a stimulus known to induce NETs formation, induce both EMT and cell death in the lung epithelial cell line, A549. Notably, NETs isolated from PMA-Neu induce EMT without cell damage. Bronchoalveolar lavage fluid of severe COVID-19 patients showed high concentration of NETs. Thus, we tested in an in vitro alveolar model the hypothesis that virus-induced NET may drive EMT. Co-culturing A549 at air-liquid interface with alveolar macrophages, neutrophils and SARS-CoV2, we demonstrated a significant induction of the EMT in A549 together with high concentration of NETs, IL8 and IL1β, best-known inducers of NETosis. Lung tissues of COVID-19 deceased patients showed that epithelial cells are characterized by increased mesenchymal markers. These results show for the first time that NETosis plays a major role in triggering lung fibrosis in COVID-19 patients.

scholarly journals Emodin Ameliorates High Glucose Induced-Podocyte Epithelial-Mesenchymal Transition In-Vitro and In-Vivo

2015 ◽  
Vol 35 (4) ◽  
pp. 1425-1436 ◽  
Author(s):  
Tingfang Chen ◽  
Li Yang Zheng ◽  
Wenzhen Xiao ◽  
Dingkun Gui ◽  
Xiaoxia Wang ◽  
...  
Keyword(s):  
High Glucose ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Option ◽  
Diabetic Rats ◽  
Protective Effects ◽  
Mesenchymal Transition ◽  
Epithelial Marker

Background: Epithelial-to-mesenchymal transition (EMT) is a potential pathway leading to podocyte depletion and proteinuria in diabetic kidney disease (DKD). Here, we investigated the protective effects of Emodin (EMO) on high glucose (HG) induced-podocyte EMT in-vitro and in-vivo. Methods: Conditionally immortalized mouse podocytes were exposed to HG with 30μg /ml of EMO and 1μmol/ml of integrin-linked kinase (ILK) inhibitor QLT0267 for 24 h. Streptozotocin (STZ)-induced diabetic rats were treated with EMO at 20 mg· kg-1· d-1 and QLT0267 at 10 mg· kg-1· w-1 p.o., for 12 weeks. Albuminuria and blood glucose level were measured. Immunohistochemistry, immunofluorescence, western blotting and real-time PCR were used to detect expression of ILK, the epithelial marker of nephrin and the mesenchymal marker of desmin in-vitro and in-vivo. Results: HG increased podocyte ILK and desmin expression while decreased nephrin expression. However, EMO significantly inhibited ILK and desmin expression and partially restored nephrin expression in HG-stimulated podocytes. These in-vitro observations were further confirmed in-vivo. Treatment with EMO for 12 weeks attenuated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. EMO also repressed renal ILK and desmin expression, preserved nephrin expression, as well as ameliorated albuminuria in STZ-induced diabetic rats. Conclusion: EMO ameliorated glucose-induced EMT and subsequent podocyte dysfunction partly through ILK and desmin inhibition as well as nephrin upregulatiotion, which might provide a potential novel therapeutic option for DKD.

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 MicroRNA-200a inhibits TGF-β-induced epithelial-mesenchymal transition in human ovarian carcinoma cells by downregulating SOX4 expression

2021 ◽  
Author(s):  
Ziyao Ren ◽  
Yonghua Hu ◽  
Jian Chen ◽  
Lanying Jin
Keyword(s):  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Lymph Node Status ◽  
Tumor Biomarker ◽  
Small Interfering Rnas ◽  
Mesenchymal Transition ◽  
Epithelial Marker ◽  
Human Ovarian Carcinoma

IntroductionThe microRNA-200 (miR-200) family and sex-determining region Y-box 4 (SOX4) could regulate EMT phenotypes, which is important to the process of tumor pathological. This study explored the association of miR-200a with SOX4 in transforming growth factor (TGF)-β-induced EMT of OC cells.Material and methodsFor the in vitro experiments, hunam CO cells subjected to TGF-β was used to induce EMT; the activity of miR-200a was selectively inhibited or overexpressioned by miR-200a inhibitor and mimics, respectively. Small interfering RNAs against SOX4 (si-SOX4) were used to inhibit SOX4 expression in human OC cell lines.ResultsDecreased miR-200a and increased SOX4 levels were detected in patients with OC and these changes were closely related to the International Federation of Gynaecology and Obstetrics stage, ovarian tumor biomarker CA125 level, lymph node status and tumor size. The TGF-β-treated cells increased the miR-200a level, decreased the SOX4 level and prompted EMT properties, including a reduction in epithelial marker (e-cadherin), induction in interstitial markers (vimentin and n-cadherin), and enhancement of proliferation, migration and invasion. The OC cells were transducted with miR-200a mimic and the overexpression cells were subsequently treated with TGF-β, decreased SOX4 expression and EMT properties were detected. Also, in miR-200a inhibited cells, TGF-β increased SOX4 expression and EMT properties. Moreover, SOX4 silencing weakened the effect of the miR-200a inhibitor.ConclusionsOverall, these results provide a link between miR-200a and SOX4 in OC pathogenesis and indicate that miRNA-200a inhibits EMT by downregulating SOX4 expression in human OC cells.

scholarly journals Gene Expression Profiling Identifies ESRP1 as a Potential Regulator of Epithelial Mesenchymal Transition in Somatotroph Adenomas from a Large Cohort of Patients with Acromegaly

2012 ◽  
Vol 97 (8) ◽  
pp. E1506-E1514 ◽  
Author(s):  
Tove Lekva ◽  
Jens Petter Berg ◽  
Stine Lyngvi Fougner ◽  
Ole Kristoffer Olstad ◽  
Thor Ueland ◽  
...  
Keyword(s):  
Tumor Size ◽  
Epithelial Mesenchymal Transition ◽  
Poor Response ◽  
Gh3 Cells ◽  
Pcr Analysis ◽  
Mesenchymal Transition ◽  
Epithelial Marker ◽  
E Cadherin

Abstract Context: The epithelial marker E-cadherin plays a crucial role in epithelial-mesenchymal transition (EMT). Decreased protein content in somatotroph adenomas has been associated with increased tumor size, invasion, and poor response to somatostatin analog (SA) treatment, but the potential mechanisms of EMT progression in these adenomas are lacking. Objective: We hypothesized that characterization of EMT-related transcripts in somatotroph adenomas could identify novel therapeutic targets in individuals with poor response to SA treatment and provide more knowledge of the mechanism of EMT progression. Patients: Fifty-three patients with acromegaly participated in the study. Research Design and Methods: We performed microarray analysis of 16 adenomas, eight with high expression and eight with low expression of E-cadherin, in order to identify EMT-related transcripts. Candidate transcripts were further explored in vivo in 53 adenomas and in vitro in a rat pituitary GH-producing cell (GH3) after exploring three models for reducing E-cadherin and inducing a mesenchymal phenotype. Results: In vivo E-cadherin mRNA expression in tumor tissue is associated negatively with tumor size and invasiveness and positively with GH and IGF-I levels in serum and response to SA treatment. Microarray and subsequent PCR analysis identify several EMT-related genes associated with E-cadherin expression. In vitro, few of these EMT-related genes were regulated by silencing E-cadherin or by TGF-β1 treatment in GH3 cells. In contrast, silencing Esrp1 in GH3 cells regulated many of the EMT-related transcripts. Conclusion: These results indicate that ESRP1 could be a master regulator of the EMT process in pituitary adenomas causing acromegaly.

Bone morphogenetic protein 7 attenuates epithelial–mesenchymal transition induced by silica

2015 ◽  
Vol 35 (1) ◽  
pp. 69-77 ◽  
Author(s):  
G Yang ◽  
Z Zhu ◽  
Y Wang ◽  
A Gao ◽  
P Niu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Bone Morphogenetic Protein ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Bone Morphogenetic Protein 7 ◽  
Mesenchymal Transition ◽  
Morphogenetic Protein ◽  
Epithelial Marker

The epithelial–mesenchymal transition (EMT) is a critical process in the pulmonary fibrosis. It has been reported that bone morphogenetic protein 7 (BMP-7) was able to reverse EMT in proximal tubular cells. Therefore, we test the hypothesis that EMT contributes to silica-induced pulmonary fibrosis and BMP-7 inhibits EMT in silica-induced pulmonary fibrosis. Progressive silica-induced pulmonary fibrosis in the rat was used as a model of silicosis. Epithelial and mesenchymal markers were measured from rat fibrotic lungs. Then the effects of BMP-7 on the EMT were further confirmed in A549 cells. There are increases of vimentin as a mesenchymal marker and decreases of E-cadherin as an epithelial marker in the silica-exposed rat lungs, which is in agreement with the A549 cells data. However, BMP-7 treatment significantly reduced expression of vimentin in the rat pulmonary fibrosis model and in A549 cells. In conclusion, EMT contributes to silica-induced pulmonary fibrosis. Meanwhile, the treatment of BMP-7 can inhibit silica-induced EMT in vitro and in vivo.

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