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Ellagic Acid Attenuates BLM-Induced Pulmonary Fibrosis via Inhibiting Wnt Signaling Pathway.

ABSTRACT: Idiopathic pulmonary fibrosis is a progressive lung disease with high mortality and limited therapy that is characterized by epithelial cell damage and fibroblast activation. Ellagic acid is a natural polyphenol compound widely found in fruits and nuts that has multiple pharmacological activities. In this study, we explored the potential effects and mechanisms of Ellagic acid on pulmonary fibrosis in vivo and in vitro. In vivo studies showed that Ellagic acid significantly alleviated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro experiments indicated that Ellagic acid could suppress Wnt signaling and attenuate Wnt3a-induced myofibroblast activation and the phosphorylation of Erk2 and Akt. Further studies showed that Ellagic acid could induce autophagy formation in myofibroblasts mainly by suppressing mTOR signaling and promoting apoptosis of myofibroblasts. In vivo experiments revealed that Ellagic acid significantly inhibited myofibroblast activation and promoted autophagy formation. Taken together, our results show that Ellagic acid effectively attenuates BLM-induced pulmonary fibrosis in mice by suppressing myofibroblast activation and promoting autophagy and apoptosis of myofibroblasts by inhibiting the Wnt signaling pathway.

SUBMITTER: Li X

PROVIDER: S-EPMC8072668 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with no effective treatment. The epithelial-mesenchymal transition (EMT) is a critical stage during the development of fibrosis. To assess the effect of sulforaphane (SFN) on the EMT and fibrosis using an in vitro transforming growth factor (TGF)-?1-induced model and an in vivo bleomycin (BLM)-induced model.In vitro studies, cell viability, and cytotoxicity were measured using a Cell Counting Kit-8. The functional TGF-?1-induced EMT and fibrosis were assessed using western blotting and a quantitative real-time polymerase chain reaction. The lungs were analyzed histopathologically in vivo using hematoxylin and eosin and Masson's trichrome staining. The BLM-induced fibrosis was characterized by western blotting and immunohistochemical analyses for fibronectin, TGF-?1, E-cadherin (E-cad), and ?-smooth muscle actin (SMA) in lung tissues.SFN reversed mesenchymal-like changes induced by TGF-?1 and restored cells to their epithelial-like morphology. The results confirmed that the expression of the epithelial marker, E-cadherin, increased after SFN treatment, while expression of the mesenchymal markers, N-cadherin, vimentin, and ?-SMA decreased in A549 cells after SFN treatment. In addition, SFN inhibited TGF-?1-induced mRNA expression of the EMT-related transcription factors, Slug, Snail, and Twist. The SFN treatment attenuated TGF-?1-induced expression of fibrosis-related proteins, such as fibronection, collagen I, collagen IV, and ?-SMA in MRC-5 cells. Furthermore, SFN reduced the TGF-?1-induced phosphorylation of SMAD2/3 protein in A549 cells and MRC-5 cells. BLM induced fibrosis in mouse lungs that was also attenuated by SFN treatment, and SFN treatment decreased BLM-induced fibronectin expression, TGF-?1 expression, and the levels of collagen I in the lungs of mice.SFN showed a significant anti-fibrotic effect in TGF-?-treated cell lines and BLM-induced fibrosis in mice. These findings showed that SFN has anti-fibrotic activity that may be considered in the treatment of IPF.

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Ellagic Acid Attenuates BLM-Induced Pulmonary Fibrosis via Inhibiting Wnt Signaling Pathway.

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