Induction of Epithelial–Mesenchymal Transition in Primary Airway Epithelial Cells from Patients with Asthma by Transforming Growth Factor-β1

Hackett, Tillie-Louise; Warner, Stephanie; Stefanowicz, Dorota; Shaheen, Furquan; Pechkovsky, Dmitri V.; Murray, Lynne A.; Argentieri, Rochelle L.; Kicic, Anthony; Stick, Stephen M.; Bai, Tony R.; Knight, Darryl A.

doi:10.1164/rccm.200811-1730oc

Cited by 348 publications

(334 citation statements)

References 57 publications

(71 reference statements)

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“…It has been considered that the loss of the epithelial marker E-cadherin and the induction of the mesenchymal marker N-cadherin are fundamental events in EMT. 25 BEAS-2B cells exposed to 10 ng/ml TGF-b up to 72 h induced a change of morphology consistent with EMT and cellular N-cadherin (brown staining, Figure 2a). When 1-20 mM kaempferol was added to epithelial cells in the presence of TGF-b, the EMT process was disturbed with concurrent diminution of cellular N-cadherin induction (Figure 2a).…”

Section: Suppression Of Lps-and Ova-triggered Induction Of Tgf-b1 By mentioning

confidence: 85%

Inhibition of airway epithelial-to-mesenchymal transition and fibrosis by kaempferol in endotoxin-induced epithelial cells and ovalbumin-sensitized mice

Gong

Cho

Shin

et al. 2014

Laboratory Investigation

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Chronic airway remodeling is characterized by structural changes within the airway wall, including smooth muscle hypertrophy, submucosal fibrosis and epithelial shedding. Epithelial-to-mesenchymal transition (EMT) is a fundamental mechanism of organ fibrosis, which can be induced by TGF-b. In the in vitro study, we investigated whether 1-20 mM kaempferol inhibited lipopolysaccharide (LPS)-induced bronchial EMT in BEAS-2B cells. The in vivo study explored demoting effects of 10-20 mg/kg kaempferol on airway fibrosis in BALB/c mice sensitized with ovalbumin (OVA). LPS induced airway epithelial TGF-b1 signaling that promoted EMT with concurrent loss of E-cadherin and induction of a-smooth muscle actin (a-SMA). Nontoxic kaempferol significantly inhibited TGF-b-induced EMT process through reversing E-cadherin expression and retarding the induction of N-cadherin and a-SMA. Consistently, OVA inhalation resulted in a striking loss of epithelial morphology by displaying myofibroblast appearance, which led to bronchial fibrosis with submucosal accumulation of collagen fibers. Oral administration of kaempferol suppressed collagen deposition, epithelial excrescency and goblet hyperplasia observed in the lung of OVA-challenged mice. The specific inhibition of TGF-b entailed epithelial protease-activated receptor-1 (PAR-1) as with 20 mM kaempferol. The epithelial PAR-1 inhibition by SCH-79797 restored E-cadherin induction and deterred a-SMA induction, indicating that epithelial PAR-1 localization was responsible for resulting in airway EMT. These results demonstrate that dietary kaempferol alleviated fibrotic airway remodeling via bronchial EMT by modulating PAR1 activation. Therefore, kaempferol may be a potential therapeutic agent targeting asthmatic airway constriction.

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Section: Suppression Of Lps-and Ova-triggered Induction Of Tgf-b1 By mentioning

confidence: 85%

Inhibition of airway epithelial-to-mesenchymal transition and fibrosis by kaempferol in endotoxin-induced epithelial cells and ovalbumin-sensitized mice

Gong

Cho

Shin

et al. 2014

Laboratory Investigation

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“…In contrast, we found that AGE inhibited TGF-β-induced ERK1/2 and SMAD2 phosphorylation, and increased SMAD7 expression, which was suppressed by TGF-β. TGF-β induces the alveolar EMT in human lung epithelial cells via a SMAD2-or SMAD3-dependent pathway (Yao et al, 2004;Kasai et al, 2005;Hackett et al, 2009) and is considered to be an important step toward fibroblastic foci formation in IPF (Thannickal et al, 2004;Gharaee-Kermani et al, 2007). SMAD7 inhibits TGF-β signaling through competitive binding to type 1 receptors, and it inhibits the activation of SMAD2/3 (Li et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of receptor for advanced glycation end products (RAGE) on the TGF-β-induced alveolar epithelial to mesenchymal transition

et al. 2011

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Idiopathic pulmonary fibrosis (IPF) is a lethal parenchymal lung disease characterized by myofibroblast proliferation. Alveolar epithelial cells (AECs) are thought to produce myofibroblasts through the epithelial to mesenchymal transition (EMT). Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptors whose activation is associated with renal fibrosis during diabetes and liver fibrosis. RAGE is expressed at low basal levels in most adult tissues except the lung. In this study, we evaluated the interaction of ligand advanced glycation end products (AGE) with RAGE during the epithelial to myofibroblast transition in rat AECs. Our results indicate that AGE inhibited the TGF-β-dependent alveolar EMT by increasing Smad7 expression, and that the effect was abolished by RAGE siRNA treatment. Thus, the induction of Smad7 by the AGE-RAGE interaction limits the development of pulmonary fibrosis by inhibiting TGF-β-dependent signaling in AECs.

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“…Furthermore, BMP2, BMP4 and BMP7 induce a mesenchymal-like morphology in normal primary airway epithelial cells (AECs) and enhance the rate of cell migration and increase α-SMA protein expression in AECs during restitution of a disrupted epithelium [3]. Others have also shown that TGF-β1 induces EMT in primary AECs and that EMT may be enhanced in asthmatic airways [80,81]. These findings lead us to hypothesise that BMP signalling is a key initiator of airway epithelial cell migration after injury and that the migration process involves a transient EMT-like phase.…”

Section: Bmp Emt and Tissue Regenerationmentioning

confidence: 99%

Regulation of epithelial to mesenchymal transition by bone morphogenetic proteins

McCormack

O’Dea

2013

Cellular Signalling

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Induction of Epithelial–Mesenchymal Transition in Primary Airway Epithelial Cells from Patients with Asthma by Transforming Growth Factor-β1

Abstract: TGF-beta1 induces EMT in a Smad3-dependent manner in primary AECs. However, in asthmatic-derived ALI-AEC cultures, the number of cells undergoing EMT is greater. These findings support the hypothesis that epithelial repair in asthmatic airways is dysregulated.

Cited by 348 publications

References 57 publications

Inhibition of airway epithelial-to-mesenchymal transition and fibrosis by kaempferol in endotoxin-induced epithelial cells and ovalbumin-sensitized mice

Inhibition of airway epithelial-to-mesenchymal transition and fibrosis by kaempferol in endotoxin-induced epithelial cells and ovalbumin-sensitized mice

Inhibitory effect of receptor for advanced glycation end products (RAGE) on the TGF-β-induced alveolar epithelial to mesenchymal transition

Regulation of epithelial to mesenchymal transition by bone morphogenetic proteins

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