Role of Endoplasmic Reticulum Stress in Epithelial–Mesenchymal Transition of Alveolar Epithelial Cells

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.

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Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00475.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. L212-L221 ◽

Cited By ~ 54

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.

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Neferine Attenuates Epithelial-Mesenchymal Transition of Alveolar Epithelial Cells via TGF-β Signaling Pathway

Chemotherapy Open access ◽

10.4172/2167-7700.1000241 ◽

2017 ◽

Vol 06 (03) ◽

Author(s):

Xianglong Kong ◽

Hui Li ◽

Qi Hu ◽

Yusheng Yan ◽

Wenfang Tang ◽

...

Keyword(s):

Epithelial Cells ◽

Signaling Pathway ◽

Epithelial Mesenchymal Transition ◽

Alveolar Epithelial Cells ◽

Mesenchymal Transition ◽

Alveolar Epithelial

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Epithelial–Mesenchymal Transition in the Pathogenesis of Idiopathic Pulmonary Fibrosis

Medicina ◽

10.3390/medicina55040083 ◽

2019 ◽

Vol 55 (4) ◽

pp. 83 ◽

Cited By ~ 23

Author(s):

Francesco Salton ◽

Maria Volpe ◽

Marco Confalonieri

Keyword(s):

Epithelial Cells ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Treatment Options ◽

Alveolar Epithelium ◽

Alveolar Epithelial Cells ◽

Mesenchymal Transition ◽

Alveolar Epithelial ◽

Serious Disease

Idiopathic pulmonary fibrosis (IPF) is a serious disease of the lung, which leads to extensive parenchymal scarring and death from respiratory failure. The most accepted hypothesis for IPF pathogenesis relies on the inability of the alveolar epithelium to regenerate after injury. Alveolar epithelial cells become apoptotic and rare, fibroblasts/myofibroblasts accumulate and extracellular matrix (ECM) is deposited in response to the aberrant activation of several pathways that are physiologically implicated in alveologenesis and repair but also favor the creation of excessive fibrosis via different mechanisms, including epithelial–mesenchymal transition (EMT). EMT is a pathophysiological process in which epithelial cells lose part of their characteristics and markers, while gaining mesenchymal ones. A role for EMT in the pathogenesis of IPF has been widely hypothesized and indirectly demonstrated; however, precise definition of its mechanisms and relevance has been hindered by the lack of a reliable animal model and needs further studies. The overall available evidence conceptualizes EMT as an alternative cell and tissue normal regeneration, which could open the way to novel diagnostic and prognostic biomarkers, as well as to more effective treatment options.

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