Nintedanib reduces ventilation‐augmented bleomycin‐induced epithelial–mesenchymal transition and lung fibrosis through suppression of the Src pathway

Li, Lifu; Kao, Kuo‐Chin; Liu, Yung-Yang; Lin, Changwei; Chen, Ning‐Hung; Lee, Chung-Shu; Wang, Chih‐Wei; Yang, Cheng‐Ta

doi:10.1111/jcmm.13206

Cited by 52 publications

(64 citation statements)

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“…Src kinase has previously been shown to be required for bcatenin phosphorylation at tyrosine residue 654 (Y654) and the initiation of EMT, and it has been correlated with increased b-catenin-dependent transcription in both A549 cells and primary AECs (Kim et al, 2009;Ulsamer et al, 2012). As mentioned previously, nintedanib significant inhibits Src family kinases (Li et al, 2017). Thus, we suspected that nintedanib could affect Wnt signaling through inhibiting Src activation in myofibroblasts.…”

Section: Nintedanib Suppressed Wnt-induced Src Activation and B-catenmentioning

confidence: 67%

Nintedanib Inhibits Wnt3a-Induced Myofibroblast Activation by Suppressing the Src/β-Catenin Pathway

Liu

Deng

et al. 2020

Front. Pharmacol.

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Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by epithelial cell damage, myofibroblast activation, and collagen deposition. Multiple studies have documented that the Wnt/b-catenin pathway is aberrantly activated in IPF and plays a vital role in myofibroblast differentiation and activation. Kinases such as Src initiate Wnt/bcatenin signaling by phosphorylating b-catenin at tyrosine residues, which facilitates bcatenin accumulation in the nucleus and promotion of fibrosis progression. Nintedanib has been approved for the treatment of IPF as a multitargeted tyrosine kinase inhibitor. Nintedanib has been demonstrated to directly block Src, and whether it attenuates pulmonary fibrosis through regulating the Wnt/b-catenin pathway remains unclear. In this study, we found that nintedanib attenuated myofibroblast activation through inhibiting the expression of genes downstream of Wnt signaling such as Cyclin D1, Wisp1, and S100a4. Further experiments showed that nintedanib inhibited Wnt3a-induced b-catenin nuclear translocation through suppressing Src kinase activation and b-catenin Y654 phosphorylation. Additionally, Src knockdown fibroblasts exhibited a phenotype similar to that of the nintedanib treatment group, and the inhibitory effects of nintedanib were consistent with those of the Src kinase inhibitor KX2-391. In summary, our study shows that nintedanib exhibits an anti-fibrosis effect, partly by inhibiting the Src/bcatenin pathway.

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Section: Nintedanib Suppressed Wnt-induced Src Activation and B-catenmentioning

confidence: 67%

Nintedanib Inhibits Wnt3a-Induced Myofibroblast Activation by Suppressing the Src/β-Catenin Pathway

Liu

Deng

et al. 2020

Front. Pharmacol.

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“…EMT is a process during which epithelial cells lose their epithelial cell marker such as E-cadherin and acquire mesenchymal characteristics as α-SMA and Collagen I. EMT has been con rmed to occur in several pathological processes, including tumor invasion [29] , acute renal injury [30] , and pulmonary brosis [31,32] . Here, we demonstrated that the EMT also developed in the lungs after LPS exposure, which was coincident with increased expression of EZH2 and H3K27me3; EZH2 inhibition signi cantly restored epithelial cellular markers and inhibited bro-proliferation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of EZH2 prevents acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype

Bao

Liu

et al. 2020

Preprint

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Background: We recently reported histone methyltransferase enhancer of zeste homolog 2 (EZH2) as a key epigenetic regulator that contributes to the dysfunction of innate immune responses to sepsis and subsequent lung injury by mediating the imbalance of macrophage polarization. However, the role of EZH2 in acute respiratory distress syndrome (ARDS)-associated fibrosis remains poorly understood. Methods: In this study, we investigated the role and mechanisms of EZH2 in pulmonary fibrosis in a murine model of LPS-induced ARDS and in ex-vivo cultured alveolar macrophages (MH-S) and mouse lung epithelial cell line (MLE-12) by using 3-deazaneplanocin A (3-DZNeP) and EZH2 the small interfering (si) RNA. Results: We found that treatment with 3-DZNeP significantly ameliorated the LPS-induced direct lung injury and fibroproliferation by blocking the epithelial to mesenchymal transition (EMT) through transforming growth factor-β1 (TGF-β1)/Smad signaling pathway and regulating shift of macrophage phenotypes. In the ex-vivo polarized alveolar macrophages cells, treatment with EZH2 siRNA or 3-DZNeP suppressed the M1 while promoted the M2 macrophage differentiation through modulating the STAT/SOCS signaling pathway and activating PPAR-γ. Moreover, we identified that blockade of EZH2 with 3-DZNeP suppressed EMT in co-cultured bronchoalveolar lavage fluid (BALF) and mouse lung epithelial cell line through down-regulation of TGF-β1, TGF-βR1, Smad2 while up-regulation of Smad7 expression. Conclusions: These results indicate that EZH2 is involved in the pathological process of ARDS-associated pulmonary fibrosis. Targeting EZH2 may be a potential therapeutic strategy to prevent and treat pulmonary fibrosis post ARDS.

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“…It exerts anti-pulmonary brosis activity by inhibiting broblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR). Studies in mice found that nintedanib reduces high tidal volume mechanical ventilation-augmented epithelial mesenchymal transition and pulmonary brosis after bleomycin-induced acute lung injury (18). Nintedanib has not been used in pulmonary brosis patients with viral pneumonia treatment, but more clinical research is needed.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary function of patients with 2019 novel coronavirus induced pneumonia: A Retrospective Cohort Study

Chen

Mao

et al. 2020

Preprint

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Background: Pulmonary fibrosis is a common complication in patients with viral pneumonia, which causes restricted ventilation disorders and affects the prognosis of patients. However, the pulmonary function of patients with 2019 novel coronavirus (COVID-19)-induced pneumonia has not yet been reported.Methods: A retrospective analysis of 137 patients with COVID-19-induced pneumonia who were discharged from the Enze Hospital, Taizhou Enze Medical Center (Group), from January 31, 2020, to March 11, 2020. Follow-up occurred two weeks after hospital discharge, whereupon patients received a pulmonary function test. Results: Of the 137 patients who received a pulmonary function test two weeks after discharge, 51.8% were male, and the mean age was 47 years. Only 19.7% of the patients were identified as having severe novel coronavirus pneumonia. The pulmonary function test showed that for a small number of patients ((FEV1/FVC)/% <70%,) the mean ICV and FVC was 2.4±0.7 L, 3.2±0.8 L, respectively. In severe cases, 88.9% of patients had an IVC <80% of the predicted value and 55.6% of patients had an FVC <80% of the predicted value. The MEF25, MEF50, and MEF75 <70% values were 55.6%, 40.7%, and 25.9%, respectively. In the non-severe group, 79.1% of patients has an IVC <80% of the predicted value, and 16.4% of patients had an FVC <80% of the predicted value. The mean MEF25, MEF50, and MEF75 <70% values were 57.3%, 30%, and 13.6%, respectively.Conclusions: In this study, the results suggest that the pulmonary function of patients with 2019 novel coronavirus (COVID-19)-induced pneumonia manifested as restrictive ventilation disorder and small airway obstruction. The incidence was increased among critically ill patients.Trial registration number: ChiCTR2000029866.

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Nintedanib reduces ventilation‐augmented bleomycin‐induced epithelial–mesenchymal transition and lung fibrosis through suppression of the Src pathway

Cited by 52 publications

References 50 publications

Nintedanib Inhibits Wnt3a-Induced Myofibroblast Activation by Suppressing the Src/β-Catenin Pathway

Nintedanib Inhibits Wnt3a-Induced Myofibroblast Activation by Suppressing the Src/β-Catenin Pathway

Inhibition of EZH2 prevents acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype

Pulmonary function of patients with 2019 novel coronavirus induced pneumonia: A Retrospective Cohort Study

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