Abstract
Pulmonary fibrosis is a chronic, progressive lung disease associated with lung damage and scarring. The pathological mechanism causing pulmonary fibrosis remains unknown. Emerging evidence suggests prominent roles of epithelial–mesenchymal transition (EMT) of alveolar epithelial cells (AECs) in myofibroblast formation and progressive pulmonary fibrosis. Our previous work has demonstrated the regulation of YY1 in idiopathic pulmonary fibrosis and pathogenesis of fibroid lung. However, the specific function of YY1 in AECs during the pathogenesis of pulmonary fibrosis is yet to be determined. Herein, we found the higher level of YY1 in primary fibroblasts than that in primary epithelial cells from the lung of mouse. A549 and BEAS-2B cells, serving as models for type II alveolar pulmonary epithelium in vitro, were used to determine the function of YY1 during EMT of AECs. TGF-β-induced activation of the pro-fibrotic program was applied to determine the role YY1 may play in pro-fibrogenesis of type II alveolar epithelial cells. Upregulation of YY1 was associated with EMT and pro-fibrotic phenotype induced by TGF-β treatment. Targeted knockdown of YY1 abrogated the EMT induction by TGF-β treatment. Enforced expression of YY1 can partly mimic the TGF-β-induced pro-fibrotic change in either A549 cell line or primary alveolar epithelial cells, indicating the induction of YY1 expression may mediate the TGF-β-induced EMT and pro-fibrosis. In addition, the translocation of NF-κB p65 from the cytoplasm to the nucleus was demonstrated in A549 cells after TGF-β treatment and/or YY1 overexpression, suggesting that NF-κB-YY1 signaling pathway regulates pulmonary fibrotic progression in lung epithelial cells. These findings will shed light on the better understanding of mechanisms regulating pro-fibrogenesis in AECs and pathogenesis of lung fibrosis.
Highlights
Pulmonary fibrosis is a chronic, progressive lung disease associated with lung damage and scarring
Upregulation of Yin Yang1 (YY1) by Transforming Growth Factor β (TGF-β) treatment in A549 cells In order to determine the mechanism regulating the pathogenesis of pulmonary fibrosis, the primary fibroblast cells and alveolar epithelial cells were isolated from the lung from either C57BL/6 mouse with Th1 immune response (Fig. 1a-c) or BALB/C mouse with Th2 immune response (Fig. 1d-f)
Further analysis on type I alveolar epithelial cells R3/1 and type II-like A549 cells indicated the fibrocyte-like morphology with long fusiform shape for R3/1 cells (Fig. 1g). 5 ng/ml of Transforming Growth Factor (TGF)-β was applied to both R3/1 and A549 cells to induce epithelial– mesenchymal transition (EMT)
Summary
Pulmonary fibrosis is a chronic, progressive lung disease associated with lung damage and scarring. The translocation of NF-κB p65 from the cytoplasm to the nucleus was demonstrated in A549 cells after TGF-β treatment and/or YY1 overexpression, suggesting that NF-κB-YY1 signaling pathway regulates pulmonary fibrotic progression in lung epithelial cells. These findings will shed light on the better understanding of mechanisms regulating pro-fibrogenesis in AECs and pathogenesis of lung fibrosis. TGF-β is upregulated and activated in fibrotic diseases It modulates fibroblast phenotype and function through inducing myofibroblast transdifferentiation, inducing EMT of AECs and promoting matrix preservation [8, 18]. TGF-β induces renal fibrosis via activation of both canonical and non-canonical signaling pathways, resulting in activation of myofibroblasts, overexpression of extracellular matrix and inhibition of ECM degradation [20]
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