Curdione ameliorates bleomycin-induced pulmonary fibrosis by repressing TGF-β-induced fibroblast to myofibroblast differentiation

Liu, Peng; Miao, Kang; Zhang, Lei; Mou, Yong; Xu, Yongjian; Xiong, Weining; Yu, Jun; Wang, Yi

doi:10.1186/s12931-020-1300-y

Cited by 68 publications

(30 citation statements)

References 26 publications

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“…Furthermore, BCA treatment significantly reduced the collagen deposition in lung sections by Ashcroft score analysis as evidenced in reduced hydroxyproline content in the lung tissues. In line with previous studies ( Gao et al., 2015 ; Liu et al., 2020 )present study also assessed the FN-I and COL1A1 expression in lung tissues, in addition to that we have also assessed the E-cad expression to check the reversal of EMT, BCA treatment dramatically reduced the BLM elevated levels of FN-I and COL1A1 and improved the E-cad levels in lung tissues ( Fig. 9 ).…”

Section: Discussionsupporting

confidence: 86%

“…Accumulating evidence suggests that, reactive oxygen species (ROS) as crucial conspirators in EMT engagement ( Giannoni et al., 2012 ). Several studies ( Liu et al., 2020 ; Yang et al., 2019 ) mainly investigated on the expression of EMT and collagen markers to evaluate the anti-fibrotic activity of test compounds. Since, BCA shows strong anti-oxidant property ( Sadri et al., 2017 ), we investigated the role of BCA against expression of EMT and ECM markers in IPF condition.…”

Section: Discussionmentioning

confidence: 99%

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Biochanin-A ameliorates pulmonary fibrosis by suppressing the TGF-β mediated EMT, myofibroblasts differentiation and collagen deposition in in vitro and in vivo systems

et al. 2020

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Background: Idiopathic Pulmonary Fibrosis (IPF) is a progressive inflammatory disorder driven by a fibrotic cascade of events such as epithelial to mesenchymal transition, extracellular matrix production and collagen formation in the lungs in a sequential manner. IPF incidences were raising rapidly across the world. FDA approved pirfenidone and nintedanib (tyrosine kinase inhibitors) are being used as a first-line treatment drugs for IPF, however, neither the quality of life nor survival rates have been improved because of patient noncompliance due to multiple side effects. Thus, the development of novel therapeutic approaches targeting TGF-β mediated cascade of fibrotic events is urgently needed to improve the survival of the patients suffering from devastating disease. Purpose: The aim of this study was to investigate and validate the anti-fibrotic properties of Biochanin-A (isoflavone) against TGF-β mediated fibrosis in in vitro, ex vivo, in vivo models and to determine the molecular mechanisms that mediate these anti-fibrotic effects. Methods: The therapeutic activity of BCA was determined in in vitro/ex vivo models. Cells were pre-treated with BCA and incubated in presence or absence of recombinant-TGF-β to stimulate the fibrotic cascade of events. Pulmonary fibrosis was developed by intratracheal administration of bleomycin in rats. BCA treatment was given for 14 days from post bleomycin instillation and then various investigations (collagen content, fibrosis gene/protein expression and histopathological changes) were performed to assess the anti-fibrotic activity of BCA. Results: In vitro/ex vivo (Primary normal, IPF cell line and primary IPF cells/ Precision cut mouse lung slices) experiments revealed that , BCA treatment significantly ( p < 0.001) reduced the expression of TGF-β modulated fibrotic genes/protein expressions (including their functions) which are involved in the cascade of fibrotic events. BCA treatment significantly ( p < 0.01) reduced the bleomycin-induced inflammatory cell-infiltration, inflammatory markers expression, collagen deposition and expression of fibrotic markers in lung tissues equivalent or better than pirfenidone treatment. In addition, BCA treatment significantly ( p < 0.001) attenuated the TGF-β1/BLM-mediated increase of TGF-β/Smad2/3 phosphorylation and resulted in the reduction of pathological abnormalities in lung tissues determined by histopathology observations. Conclusion: Collectively, BCA treatment demonstrated the remarkable therapeutic effects on TGF-β/BLM mediated pulmonary fibrosis using IPF cells and rodent models. This current study may offer a novel treatment approach to halt and may be even rescue the devastating lung scarring of IPF.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Biochanin-A ameliorates pulmonary fibrosis by suppressing the TGF-β mediated EMT, myofibroblasts differentiation and collagen deposition in in vitro and in vivo systems

et al. 2020

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“…The left lungs were inflated with 4% neutral buffered paraformaldehyde and then fixed in the above fluid for 24 h at room temperature, followed by paraffin embedding. The lung tissues were sliced into 5 µm sections and stained with hematoxylin and eosin (H&E) 24 , Sirius red and Masson's trichrome as previously reported 25 , 26 . The severity of pulmonary fibrosis was scored on a scale from 0 to 8 based on the Ashcroft scale.…”

Section: Methodsmentioning

confidence: 99%

Suppressing Sart1 to modulate macrophage polarization by siRNA-loaded liposomes: a promising therapeutic strategy for pulmonary fibrosis

et al. 2021

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Idiopathic pulmonary fibrosis (IPF) is a chronic and diffuse form of interstitial lung disease of unknown etiology with a fatal outcome. Although various strategies for IPF have been developed over the last few decades, no significant positive impact on the prognosis of IPF has been observed. According to the current paradigm, macrophages have been recognized to play a significant role in IPF pathogenesis. Here, we report a potential nanomedicine-based gene therapy for IPF based on regulate macrophage polarization. Method: C57BL/6 mice were obtained and used to establish a bleomycin (BLM)-induced pulmonary fibrosis animal model, and Sart1 siRNA-loaded liposomes were designed for in vivo experiment. The experimental animals were administered BLM intratracheally on day 0 and treated with Sart1 siRNA on days 14 and 17. In the in vitro experiment, we further examined the function of Sart1 in macrophages. Results: Our data indicated that the liposomes could passively target the fibrotic area in the lung and efficiently accumulate in macrophages. The suppression of Sart1 by siRNA-loaded liposomes significantly protected mice against BLM-induced lung injury and fibrosis, which was attributed to attenuated M2 macrophage infiltration in the lung. Conclusion: Our study provides a valuable reference for modulating macrophage polarization and a promising strategy for the treatment of pulmonary fibrosis in clinical settings.

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“…The sections were then stained with hematoxylin and eosin (H&E), Masson's trichrome stain and Sirius red as previously described 23 . Fibrosis was scored on a scale of 0-8 using the Ashcroft scoring method 24 . The severity of brotic changes in each histological section of the lung was assessed as the mean of the severity scores from the observed microscopic elds.…”

Section: Pathological Staining and Histopathologic Assessmentmentioning

confidence: 99%

“…Primary human pulmonary broblasts (PHLFs) were isolated from para-carcinoma lung tissues resected from NSCLC patients, and primary mouse pulmonary broblasts (PMLFs) were isolated from the lung tissues of Acp5 -/or WT mice as described previously 24,26 . Brie y, broblasts were generated by mincing lung tissue into submillimeter-sized pieces, plated evenly in 100 mm plates containing 2 ml of medium, which was changed after 24 hours.…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

Tartrate-resistant acid phosphatase 5 serves as a viable target against pulmonary fibrosis by modulating β-catenin signaling

Hu¹,

Yu²,

Wang³

et al. 2020

Preprint

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Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Tartrate-resistant acid phosphatase 5 (ACP5) performs a variety of functions. However, its role in IPF remains unclear. Here, we demonstrated that the levels of ACP5 were increased in IPF patient samples and mice with bleomycin (BLM)-induced pulmonary fibrosis. In particular, higher levels of ACP5 were noted in the sera of IPF patients with a diffusing capacity of the lungs for carbon monoxide (DLCO) less than 40% of the predicted value. Additionally, Acp5 deficiency protected mice from BLM-induced lung injury and fibrosis and reduced the differentiation and proliferation of fibroblasts. Mechanistic studies revealed that Acp5 was upregulated by TGF-β1 in a TGFβR1/Smad3-dependent manner, after which Acp5 dephosphorylated p-β-catenin at Ser33 and Thr41, inhibiting the degradation of β-catenin and subsequently enhancing β-catenin signaling in the nucleus, which promoted the differentiation and proliferation of fibroblast. Notably, the treatment of mice with BLM-induced fibrosis with Acp5 siRNA-loaded liposomes robustly reversed lung fibrosis. Collectively, these data indicate that Acp5 plays an essential role in the initiation and progression of pulmonary fibrosis; therefore, strategies aimed at silencing Acp5 could be novel therapeutic approaches against pulmonary fibrosis in a clinical setting.

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Curdione ameliorates bleomycin-induced pulmonary fibrosis by repressing TGF-β-induced fibroblast to myofibroblast differentiation

Cited by 68 publications

References 26 publications

Biochanin-A ameliorates pulmonary fibrosis by suppressing the TGF-β mediated EMT, myofibroblasts differentiation and collagen deposition in in vitro and in vivo systems

Biochanin-A ameliorates pulmonary fibrosis by suppressing the TGF-β mediated EMT, myofibroblasts differentiation and collagen deposition in in vitro and in vivo systems

Suppressing Sart1 to modulate macrophage polarization by siRNA-loaded liposomes: a promising therapeutic strategy for pulmonary fibrosis

Tartrate-resistant acid phosphatase 5 serves as a viable target against pulmonary fibrosis by modulating β-catenin signaling

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