Dihydromyricetin Alleviates Pulmonary Fibrosis by Regulating Abnormal Fibroblasts Through the STAT3/p-STAT3/GLUT1 Signaling Pathway.

Zhen Li,Chen Wang,Bingbing Xie,Jing Geng,Jing Wang,Jiarui He,Huaping Dai,Liang Peng,Yinan Hu

doi:10.3389/fphar.2022.834604

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disorder with a poor prognosis. Although dihydromyricetin (DHM), extracted from vine tea and other Ampelopsis species, has been proven to have anti-inflammatory and antioxidant functions, the effects of DHM on IPF remain unclear. Methods: The effects of DHM on the differentiation, migration, proliferation, and respiratory functions of primary mouse lung fibroblasts (PMLFs) and primary human lung fibroblasts (PHLFs) were detected by western blotting, the Transwell assay, EdU staining, and the Mito Stress test. Then, the impacts of DHM on bleomycin (BLM)-induced pulmonary fibrosis were evaluated by pathological staining, western blotting, and coimmunofluorescence staining. The signaling pathway influenced by DHM was also investigated. Results: DHM could regulate the differentiation of fibroblasts to myofibroblasts and suppress the abnormal migration, proliferation, and respiratory functions of myofibroblasts induced by TGF-β1 or myofibroblasts from IPF patients. DHM could also alleviate pulmonary fibrosis induced by BLM. All these effects were achieved by regulating the STAT3/p-STAT3/GLUT1 signaling pathway. Conclusion: DHM could regulate the abnormal functions of myofibroblasts induced by TGF-β1 and myofibroblasts from IPF patients and alleviate pulmonary fibrosis induced by BLM; thus, DHM might be a candidate medicinal treatment for IPF.

Highlights

Idiopathic pulmonary fibrosis (IPF), characterized by chronic and progressive fibrosis of the interstitial lung tissue, is an irreversible and fatal lung disease with a poor prognosis (Richeldi et al, 2017)
The Cell Counting Kit-8 (CCK-8) assay revealed that the IC50 of DHM was 628 μM in Primary mouse lung fibroblasts (PMLFs) (Figure 2A) and 7556 μM in Primary human lung fibroblasts (PHLFs) (Figure 2B)
All these results revealed that DHM could attenuate the differentiation of fibroblasts to myofibroblasts induced by TGF-β1 and lead to the dedifferentiation of IPF-HLFs, indicating that DHM may be effective for preventing pulmonary fibrosis and restoring the fibrotic lung tissue in clinical applications

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF), characterized by chronic and progressive fibrosis of the interstitial lung tissue, is an irreversible and fatal lung disease with a poor prognosis (Richeldi et al, 2017). The precise initiation factors that lead to these disorders remain unknown, it is widely recognized that the pathological process of IPF is related to fibroblasts and myofibroblasts (Chanda et al, 2019). Previous studies have suggested that various cytokines, such as the transform growth factor (TGF-β), and signaling pathways, such as the STAT/pSTAT3 pathway, can promote fibroblast differentiation into myofibroblasts and result in fibrosis of the lung tissue (Zehender et al, 2018). For this reason, restraining the differentiation of fibroblasts into myofibroblasts may block the initiation of fibrosis, while reversing this differentiation process might lead to a breakthrough treatment for IPF (Wei et al, 2019). Dihydromyricetin (DHM), extracted from vine tea and other Ampelopsis species, has been proven to have anti-inflammatory and antioxidant functions, the effects of DHM on IPF remain unclear

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Discussion

Conclusion