FGF-1 reverts epithelial-mesenchymal transition induced by TGF-β1 through MAPK/ERK kinase pathway

2010 ◽  
Vol 299 (2) ◽  
pp. L222-L231 ◽  
Author(s):  
Carlos Ramos ◽  
Carina Becerril ◽  
Martha Montaño ◽  
Carolina García-De-Alba ◽  
Remedios Ramírez ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Morphological Changes ◽  
Smooth Muscle Actin ◽  
Substantial Reduction ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Opposite Process ◽  
Kinase Pathway ◽  
Tgf Β1 ◽  
Erk Kinase

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterized by the expansion of the fibroblast/myofibroblast population and aberrant remodeling. However, the origin of mesenchymal cells in this disorder is still under debate. Recent evidence indicates that epithelial-mesenchymal transition (EMT) induced primarily by TGF-β1 plays an important role; however, studies regarding the opposite process, mesenchymal-epithelial transition, are scanty. We have previously shown that fibroblast growth factor-1 (FGF-1) inhibits several profibrogenic effects of TGF-β1. In this study, we examined the effects of FGF-1 on TGF-β1-induced EMT. A549 and RLE-6TN (human and rat) alveolar epithelial-like cell lines were stimulated with TGF-β1 for 72 h, and then, in the presence of TGF-β1, were cultured with FGF-1 plus heparin for an additional 48 h. After TGF-β1 treatment, epithelial cells acquired a spindle-like mesenchymal phenotype with a substantial reduction of E-cadherin and cytokeratins and concurrent induction of α-smooth muscle actin measured by real-time PCR, Western blotting, and immunocytochemistry. FGF-1 plus heparin reversed these morphological changes and returned the epithelial and mesenchymal markers to control levels. Signaling pathways analyzed by selective pharmacological inhibitors showed that TGF-β1 induces EMT through Smad pathway, while reversion by FGF-1 occurs through MAPK/ERK kinase pathway, resulting in ERK-1 phosphorylation and Smad2 dephosphorylation. These findings indicate that TGF-β1-induced EMT is reversed by FGF-1 and suggest therapeutic approaches to target this process in IPF.

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.

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 RhoA-Dependent HGF and c-Met Mediate Gas6-Induced Inhibition of Epithelial–Mesenchymal Transition, Migration, and Invasion of Lung Alveolar Epithelial Cells

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 565 ◽  
Author(s):  
Jung ◽  
Yang ◽  
Kim ◽  
Lee ◽  
Kim ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Rho Kinase ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Tgf Β1

Previously, we demonstrated that growth arrest-specific protein 6 (Gas6)/Axl or Mer signaling inhibited the transforming growth factor (TGF)-β1-induced epithelial–mesenchymal transition (EMT) in lung epithelial cells. Hepatocyte growth factor (HGF) has also been shown to inhibit TGF-β1-induced changes in EMT markers. Here, we examined whether Gas6 signaling can induce the production of HGF and c-Met in lung alveolar epithelial cells to mediate the inhibition of EMT and to inhibit the migration and invasion of epithelial cells. The inhibition of the RhoA/Rho kinase pathway, using either a RhoA-targeted small interfering RNA (siRNA) or the Rho kinase pharmacologic inhibitor Y27362, prevented the inhibition of TGF-β1-induced EMT in LA-4 cells and primary alveolar type II (AT II) epithelial cells. The c-Met antagonist PHA-665752 also blocked the anti-EMT effects associated with Gas6. Moreover, treatment with Y27362 or PHA-665752 prevented the Gas6-mediated inhibition of TGF-β1-induced migration and invasion. Our data provided evidence that the RhoA-dependent production of HGF and c-Met mediated the Gas6-induced inhibition of EMT, migration and invasion in lung alveolar epithelial cells. Thus, Gas6/Axl and Mer/RhoA signaling may be necessary for the maintenance of homeostasis in the alveolar epithelium, via HGF and c-Met.

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.

Sarcomatoid carcinoma represents a complete phenotype with various pathways of epithelial mesenchymal transition

2013 ◽  
Vol 66 (7) ◽  
pp. 601-606 ◽  
Author(s):  
Chang Ohk Sung ◽  
Hannah Choi ◽  
Keun-Woo Lee ◽  
Seok-Hyung Kim
Keyword(s):  
Transcription Factors ◽  
Epithelial Mesenchymal Transition ◽  
Morphological Changes ◽  
Smooth Muscle Actin ◽  
Expression Patterns ◽  
Sarcomatoid Carcinoma ◽  
Phenotypic Markers ◽  
Mesenchymal Transition ◽  
Related Phenotype ◽  
Phenotype Markers

AimsSarcomatoid carcinoma (SC) is considered to be a result of the sarcomatoid change of epithelial carcinoma. However, epithelial–mesenchymal transition (EMT) in SC has been insufficiently studied.MethodsWe evaluated the expression patterns of EMT-related phenotypic markers with transcription factors in 27 SCs originating from various organs, and we investigated the phenotypic characteristics of SCs classified as complete, incomplete or wild-type. We further analysed correlations between EMT-related phenotype markers and transcription factors.ResultsEpithelial markers (E-cadherin, claudin-3 and claudin-4) were consistently down-regulated, whereas mesenchymal markers (S100A4, α-smooth muscle actin (SMA), vimentin, PDGFRα and β-catenin) were variously expressed except for vimentin. EMT-related transcription factors (SIP1, Snail1, Slug, Twist1, ZEP1 and Oct-4) also showed various expression patterns. The expression patterns of phenotypic markers showed that most SCs (22/27, 81.5%, 95% CI 65.8 to 97.1%) had complete EMT phenotypes, whereas the remaining 5 (18.5%, 95% CI 2.8 to 24.1%) were of incomplete type. Unsupervised hierarchical clustering analysis revealed that SCs were clustered into several subgroups by EMT-related protein expression pattern. Twist1 positivity was significantly concordant with α-SMA positivity (κ value: 0.908; 95% CI 0.73 to 1.00, p<0.001, adjusted p<0.001). The EMT phenotypes of SC were simple, with complete phenotype being the predominant form, and the morphological changes of the SCs were also relevant in terms of EMT.ConclusionsSC seems to be an irreversible, permanent change in the EMT phenomenon, with complete EMT phenotypes and various EMT-related pathways being involved in SC.

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