scholarly journals Role of Smad2/3 and p38 MAP kinase in TGF-β1-induced epithelial-mesenchymal transition of pulmonary epithelial cells

2011 ◽  
Vol 226 (5) ◽  
pp. 1248-1254 ◽  
Author(s):  
Irina Kolosova ◽  
David Nethery ◽  
Jeffrey A. Kern
Keyword(s):  
Epithelial Cells ◽  
Map Kinase ◽  
Epithelial Mesenchymal Transition ◽  
P38 Map Kinase ◽  
Mesenchymal Transition ◽  
Pulmonary Epithelial Cells ◽  
Tgf Β1

scholarly journals Expression and Activity of Phosphodiesterase Isoforms during Epithelial Mesenchymal Transition: The Role of Phosphodiesterase 4

2009 ◽  
Vol 20 (22) ◽  
pp. 4751-4765 ◽  
Author(s):  
Ewa Kolosionek ◽  
Rajkumar Savai ◽  
Hossein Ardeschir Ghofrani ◽  
Norbert Weissmann ◽  
Andreas Guenther ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Critical Event ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Phenotype Markers ◽  
Tgf Β1 ◽  
E Cadherin

Epithelial–mesenchymal transition (EMT) has emerged as a critical event in the pathogenesis of organ fibrosis and cancer and is typically induced by the multifunctional cytokine transforming growth factor (TGF)-β1. The present study was undertaken to evaluate the potential role of phosphodiesterases (PDEs) in TGF-β1-induced EMT in the human alveolar epithelial type II cell line A549. Stimulation of A549 with TGF-β1 induced EMT by morphological alterations and by expression changes of the epithelial phenotype markers E-cadherin, cytokeratin-18, zona occludens-1, and the mesenchymal phenotype markers, collagen I, fibronectin, and α-smooth muscle actin. Interestingly, TGF-β1 stimulation caused twofold increase in total cAMP-PDE activity, contributed mostly by PDE4. Furthermore, mRNA and protein expression demonstrated up-regulation of PDE4A and PDE4D isoforms in TGF-β1-stimulated cells. Most importantly, treatment of TGF-β1 stimulated epithelial cells with the PDE4-selective inhibitor rolipram or PDE4 small interfering RNA potently inhibited EMT changes in a Smad-independent manner by decreasing reactive oxygen species, p38, and extracellular signal-regulated kinase phosphorylation. In contrast, the ectopic overexpression of PDE4A and/or PDE4D resulted in a significant loss of epithelial marker E-cadherin but did not result in changes of mesenchymal markers. In addition, Rho kinase signaling activated by TGF-β1 during EMT demonstrated to be a positive regulator of PDE4. Collectively, the findings presented herein suggest that TGF-β1 mediated up-regulation of PDE4 promotes EMT in alveolar epithelial cells. Thus, targeting PDE4 isoforms may be a novel approach to attenuate EMT-associated lung diseases such as pulmonary fibrosis and lung cancer.

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.

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.

scholarly journals The Crosstalk between Nrf2 and TGF-β1 in the Epithelial-Mesenchymal Transition of Pancreatic Duct Epithelial Cells

PLoS ONE ◽  
2015 ◽  
Vol 10 (7) ◽  
pp. e0132978 ◽  
Author(s):  
Sarah Arfmann-Knübel ◽  
Birte Struck ◽  
Geeske Genrich ◽  
Ole Helm ◽  
Bence Sipos ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pancreatic Duct ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Tgf Β1

Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells

2007 ◽  
Vol 293 (1) ◽  
pp. L212-L221 ◽  
Author(s):  
Shilpa Vyas-Read ◽  
Philip W. Shaul ◽  
Ivan S. Yuhanna ◽  
Brigham C. Willis
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Alveolar Epithelial Cells ◽  
No Production ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Oxide Synthase ◽  
Tgf Β1

Patients with interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF) and bronchopulmonary dysplasia (BPD), suffer from lung fibrosis secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. Transforming growth factor (TGF)-β1 induces epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide (NO) attenuates ECM accumulation, enhances lung growth, and decreases alveolar myofibroblast number in experimental models. We therefore hypothesized that NO attenuates TGF-β1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) are expressed and active in AEC. Total NOS activity was 1.3 pmol·mg protein−1·min−1 with 67% derived from eNOS. TGF-β1 (50 pM) suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with l-NAME led to spontaneous EMT, manifested by increased α-smooth muscle actin (α-SMA) expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-β1-treated AEC decreased stress fiber-associated α-SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF-β alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as IPF and BPD.

Formin mDia1 contributes to migration and epithelial‐mesenchymal transition of tubular epithelial cells exposed to TGF‐β1

2019 ◽  
Vol 121 (8-9) ◽  
pp. 3861-3870 ◽  
Author(s):  
Yu‐Ying Li ◽  
Guo‐Tao Jiang ◽  
Li‐Jie Chen ◽  
Yan‐Hong Jiang ◽  
Jun‐Dong Jiao
Keyword(s):  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Tubular Epithelial Cells ◽  
Mesenchymal Transition ◽  
Tgf Β1

scholarly journals Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Epithelial–Mesenchymal Transition

2019 ◽  
Vol 20 (19) ◽  
pp. 4813 ◽  
Author(s):  
Sevindzh Kletukhina ◽  
Olga Neustroeva ◽  
Victoria James ◽  
Albert Rizvanov ◽  
Marina Gomzikova
Keyword(s):  
Epithelial Cells ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Epithelial Mesenchymal Transition ◽  
Genetic Material ◽  
Biologically Active ◽  
Target Cells ◽  
Mesenchymal Transition ◽  
New Evidence

Epithelial–mesenchymal transition (EMT) is a process that takes place during embryonic development, wound healing, and under some pathological processes, including fibrosis and tumor progression. The molecular changes occurring within epithelial cells during transformation to a mesenchymal phenotype have been well studied. However, to date, the mechanism of EMT induction remains to be fully elucidated. Recent findings in the field of intercellular communication have shed new light on this process and indicate the need for further studies into this important mechanism. New evidence supports the hypothesis that intercellular communication between mesenchymal stroma/stem cells (MSCs) and resident epithelial cells plays an important role in EMT induction. Besides direct interactions between cells, indirect paracrine interactions by soluble factors and extracellular vesicles also occur. Extracellular vesicles (EVs) are important mediators of intercellular communication, through the transfer of biologically active molecules, genetic material (mRNA, microRNA, siRNA, DNA), and EMT inducers to the target cells, which are capable of reprogramming recipient cells. In this review, we discuss the role of intercellular communication by EVs to induce EMT and the acquisition of stemness properties by normal and tumor epithelial cells.

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