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Scutellarein inhibits BLM-mediated pulmonary fibrosis by affecting fibroblast differentiation, proliferation, and apoptosis.

ABSTRACT: Introduction:Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease that has a poor prognosis. Scutellarein, which is extracted from the traditional Chinese medicine Erigeron breviscapus, is used to treat a variety of diseases; however, the use of scutellarein for the treatment of pulmonary fibrosis and the related mechanisms of action have not been fully explored. Methods:This study was conducted using a well-established mouse model of pulmonary fibrosis induced by bleomycin (BLM). The antifibrotic effects of scutellarein on histopathologic manifestations and fibrotic marker expression levels were examined. The effects of scutellarein on fibroblast differentiation, proliferation, and apoptosis and on related signaling pathways were next investigated to demonstrate the underlying mechanisms. Results:In the present study, we found that scutellarein alleviated BLM-induced pulmonary fibrosis, as indicated by histopathologic manifestations and the expression levels of fibrotic markers. Further data demonstrated that the ability of fibroblasts to differentiate into myofibroblasts was attenuated in scutellarein-treated mice model. In addition, we obtained in vitro evidence that scutellarein inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-?/Smad signaling, inhibited cellular proliferation by repressing PI3K/Akt signaling, and increased apoptosis of fibroblasts by affecting Bax/Bcl2 signaling. Discussion:In general, scutellarein might exert therapeutic effects on pulmonary fibrosis by altering the differentiation, proliferation, and apoptosis of fibroblasts. Although scutellarein has been demonstrated to be safe in mice, further studies are required to investigate the efficacy of scutellarein in patients with IPF.

SUBMITTER: Miao K

PROVIDER: S-EPMC7418478 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Scutellarein inhibits BLM-mediated pulmonary fibrosis by affecting fibroblast differentiation, proliferation, and apoptosis.

Miao Kang K Pan Ting T Mou Yong Y Zhang Lei L Xiong Weining W Xu Yongjian Y Yu Jun J Wang Yi Y

Therapeutic advances in chronic disease 20200730

<h4>Introduction</h4>Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease that has a poor prognosis. Scutellarein, which is extracted from the traditional Chinese medicine <i>Erigeron breviscapus</i>, is used to treat a variety of diseases; however, the use of scutellarein for the treatment of pulmonary fibrosis and the related mechanisms of action have not been fully explored.<h4>Methods</h4>This study was conducted using a well-established mouse ...[more]

PMID: 32843954

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Project description:Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin-induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double-transgenic (DTG) mice with doxycycline-inducible overexpression of human FGF2 (SPC-rtTA;TRE-hFGF2) or single-transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild-type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline-induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGFβ1-induced expression of alpha smooth muscle actin (αSMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad-dependent gene expression, FGF2 inhibited TGFβ1-induced stress fiber formation and serum response factor-dependent gene expression. FGF2 inhibition of stress fiber formation and αSMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin-induced pulmonary fibrosis in vivo and reverses TGFβ1-induced collagen and αSMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Project description:BackgroundRecent studies have highlighted the contribution of senescent mesenchymal and epithelial cells in Idiopathic Pulmonary Fibrosis (IPF), but little is known regarding the molecular mechanisms that regulate the accumulation of senescent cells in this disease. Therefore, we addressed the hypothesis that the loss of DNA repair mechanisms mediated by DNA protein kinase catalytic subunit (DNA-PKcs) in IPF, promoted the accumulation of mesenchymal progenitors and progeny, and the expression of senescent markers by these cell types.MethodsSurgical lung biopsy samples and lung fibroblasts were obtained from patients exhibiting slowly, rapidly or unknown progressing IPF and lung samples lacking any evidence of fibrotic disease (i.e. normal; NL). The expression of DNA-Pkcs in lung tissue was assessed by quantitative immunohistochemical analysis. Chronic inhibition of DNA-PKcs kinase activity was mimicked using a highly specific small molecule inhibitor, Nu7441. Proteins involved in DNA repair (stage-specific embryonic antigen (SSEA)-4+ cells) were determined by quantitative Ingenuity Pathway Analysis of transcriptomic datasets (GSE103488). Lastly, the loss of DNA-PKc was modeled in a humanized model of pulmonary fibrosis in NSG SCID mice genetically deficient in PRKDC (the transcript for DNA-PKcs) and treated with Nu7441.ResultsDNA-PKcs expression was significantly reduced in IPF lung tissues. Chronic inhibition of DNA-PKcs by Nu7441 promoted the proliferation of SSEA4+ mesenchymal progenitor cells and a significant increase in the expression of senescence-associated markers in cultured lung fibroblasts. Importantly, mesenchymal progenitor cells and their fibroblast progeny derived from IPF patients showed a loss of transcripts encoding for DNA damage response and DNA repair components. Further, there was a significant reduction in transcripts encoding for PRKDC (the transcript for DNA-PKcs) in SSEA4+ mesenchymal progenitor cells from IPF patients compared with normal lung donors. In SCID mice lacking DNA-PKcs activity receiving IPF lung explant cells, treatment with Nu7441 promoted the expansion of progenitor cells, which was observed as a mass of SSEA4+ CgA+ expressing cells.ConclusionsTogether, our results show that the loss of DNA-PKcs promotes the expansion of SSEA4+ mesenchymal progenitors, and the senescence of their mesenchymal progeny.

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Scutellarein inhibits BLM-mediated pulmonary fibrosis by affecting fibroblast differentiation, proliferation, and apoptosis.

Publications

Scutellarein inhibits BLM-mediated pulmonary fibrosis by affecting fibroblast differentiation, proliferation, and apoptosis.

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