Inhibition of Wnt/β-catenin signaling suppresses bleomycin-induced pulmonary fibrosis by attenuating the expression of TGF-β1 and FGF-2

Chen, Xiang; Shi, Chaowen; Meng, Xiannan; Zhang, Kaijia; Li, Xiaoyao; Wang, Cong; Zou, Xiang; Hu, Kebin; Han, Xiaodong

doi:10.1016/j.yexmp.2016.04.003

Cited by 61 publications

(49 citation statements)

References 45 publications

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“…Previous studies showed that bFGF and TGF-β1 play crucial roles in EMT and fibrosis [27,28]. Consistent with previous studies, our data also show that the cell morphology of bFGF-or TGF-β1-treated A549 cells was more scattered, slender and fibroblast-like (Figure 2A).…”

Section: Both Bfgf and Tgf-β1 Promoted Emt In A549 Cellssupporting

confidence: 92%

“…Among the numerous pulmonary fibrosis/EMT models, the most common and successful model is bleomycin-induced pulmonary fibrosis/EMT, both in vivo and in vitro [17,24,36]. Previous studies verified that BLM can induce EMT of A549 cells via the TGF-β1/Smad signaling pathway and can increase the expression of bFGF and TGF-β1 [28]. In our results, the BLM-induced pulmonary fibrosis model was displayed by histology and immunohistochemistry staining.…”

Section: Pulmonary Fibrosis Inducer Bleomycin Regulates Esrp By Incsupporting

confidence: 62%

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Bleomycin induces epithelial-to-mesenchymal transition via bFGF/PI3K/ESRP1 signaling in pulmonary fibrosis

Weng

Chen

et al. 2020

Bioscience Reports

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Idiopathic pulmonary fibrosis (IPF) is a fatal and chronic disease with a high rate of infection and mortality; however, its etiology and pathogenesis remain unclear. Studies have revealed that epithelial-mesenchymal transition (EMT) is a crucial cellular event in IPF. Here, we identified that the pulmonary fibrosis inducer bleomycin simultaneously increased the expression of bFGF and TGF-β1 and inhibited epithelial-specific regulatory protein (ESRP1) expression in vivo and in vitro. In addition, in vitro experiments showed that bFGF and TGF-β1 down-regulated the expression of ESRP1 and that silencing ESRP1 promoted EMT in A549 cells. Notably, we determined that bFGF activates PI3K/Akt signaling, and treatment with the PI3K/Akt inhibitor LY294002 inhibited bleomycin-induced cell morphology changes and EMT. In addition, the effects of LY294002 on bleomycin-induced EMT were inhibited by ESRP1 silencing in A549 cells. Taken together, these findings suggest that bleomycin induced EMT through down-regulating ESRP1 by simultaneously increasing bFGF and TGF-β1 in pulmonary fibrosis. Additionally, our findings indicated that bFGF inhibits ESRP1 by activating PI3K/Akt signaling.

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Section: Both Bfgf and Tgf-β1 Promoted Emt In A549 Cellssupporting

confidence: 92%

Section: Pulmonary Fibrosis Inducer Bleomycin Regulates Esrp By Incsupporting

confidence: 62%

Bleomycin induces epithelial-to-mesenchymal transition via bFGF/PI3K/ESRP1 signaling in pulmonary fibrosis

Weng

Chen

et al. 2020

Bioscience Reports

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“…New studies showed that lncRNAs act as key ceRNAs [ 14 , 23 , 24 ], thereby greatly enhancing the functionality of lncRNAs. In the present study, we demonstrated that XIST inversely regulated miR-139 expression by directly binding; in addition, β-catenin, an essential factor in Wnt/β-catenin signaling which has been reported to play a promotive role in PF [ 25 – 27 ], could directly bind to miR-139 on an almost identical binding site. These data suggested that XIST might compete with β-catenin for miR-139 binding during PF progression so as to repress the inhibitory effect of miR-139 on β-catenin, which inspired us to further investigate the detailed function of miR-139 in PF.…”

Section: Discussionsupporting

confidence: 53%

XIST/miR-139 axis regulates bleomycin (BLM)-induced extracellular matrix (ECM) and pulmonary fibrosis through β-catenin

et al. 2017

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Pulmonary fibrosis (PF), characterized by the destruction of lung tissue architecture and the abnormal deposition of extracellular matrix (ECM) proteins, currently has no satisfactory treatment. In the present study, we investigated the hypothesis that XIST play a promotive role in bleomycin (BLM)-induced ECM and pulmonary fibrosis; XIST exerts its effect through miR-139 regulation. XIST expression was upregulated in lung tissues derived from BLM-induced mouse model of PF, and was positively correlated with β-catenin and ECM protein levels, respectively. LV-sh-XIST-induced XIST knockdown led to decreased PF, reduced β-catenin and ECM protein levels in lung tissues. XIST knockdown suppressed the proliferation of IMR-90 (human fibroblast) and murine lung fibroblasts (MLFCs) and ECM protein expression. Moreover, miR-139 could directly bind to XIST and the 3’UTR of β-catenin; XIST competed with β-catenin for miR-139 binding both in IMR-90 and MLFCs. In MLFCs, miR-139 inversely regulated XIST, and could partially reverse the effect of XIST on β-catenin and ECM proteins. In lung tissues of PF mice, miR-139 expression was downregulated, whereas β-catenin expression was upregulated. In conclusion, XIST exerts positive effects on BLM-induced PF through inhibiting miR-139 to promote human/mouse fibroblast proliferation and ECM proteins.

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“…Of note, Wnt/ β -catenin pathway blocking-mediated attenuation of bleomycin-induced PF was accompanied by a decreased expression of TGF- β 1 and fibroblast growth factor (FGF) 2 in vitro and in vivo. These results support that controlling the aberrant expression of TGF- β 1 and FGF2 via inhibition of Wnt/ β -catenin signaling could serve as a potential therapeutic strategy for PF [71]. Collagen triple helix repeat containing 1 (CTHRC1) protein showed the potential to inhibit Smad2/3 activation and alleviate bleomycin-induced fibrosis in mice [105].…”

Section: Wnt Signaling Pathways As Targets For Copd and Ipf Treatmmentioning

confidence: 61%

Distinct Roles of Wnt/β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Shi

Luo

et al. 2017

Mediators of Inflammation

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Wnt signaling pathways are tightly controlled under a physiological condition, under which they play key roles in many biological functions, including cell fate specification and tissue regeneration. Increasing lines of evidence recently demonstrated that a dysregulated activation of Wnt signaling, particularly the Wnt/β-catenin signaling, was involved in the pathogenesis of chronic pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In this respect, Wnt signaling interacts with other cellular signaling pathways to regulate the initiation and pathogenic procedures of airway inflammation and remodeling, pulmonary myofibroblast proliferation, epithelial-to-mesenchymal transition (EMT), and development of emphysema. Intriguingly, Wnt/β-catenin signaling is activated in IPF; an inhibition of this signaling leads to an alleviation of pulmonary inflammation and fibrosis in experimental models. Conversely, Wnt/β-catenin signaling is inactivated in COPD tissues, and its reactivation results in an amelioration of airspace enlargement with a restored alveolar epithelial structure and function in emphysema models. These studies thus imply distinct mechanisms of Wnt/β-catenin signaling in the pathogenesis of these two chronic pulmonary diseases, indicating potential targets for COPD and IPF treatments. This review article aims to summarize the involvement and pathogenic roles of Wnt signaling pathways in the COPD and IPF, with a focus on the implication of Wnt/β-catenin signaling as underlying mechanisms and therapeutic targets in these two incurable diseases.

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Inhibition of Wnt/β-catenin signaling suppresses bleomycin-induced pulmonary fibrosis by attenuating the expression of TGF-β1 and FGF-2

Cited by 61 publications

References 45 publications

Bleomycin induces epithelial-to-mesenchymal transition via bFGF/PI3K/ESRP1 signaling in pulmonary fibrosis

Bleomycin induces epithelial-to-mesenchymal transition via bFGF/PI3K/ESRP1 signaling in pulmonary fibrosis

XIST/miR-139 axis regulates bleomycin (BLM)-induced extracellular matrix (ECM) and pulmonary fibrosis through β-catenin

Distinct Roles of Wnt/β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

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