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

Xiaohe Li,Yanhua Wang,Bo Yang,Jingjing Liang,Guang Yang,Hao Ruan,Ling Ma,Xiaowei Liu,Hailong Li,Shuyang Wu,Jingjing Gao,Kai Huang,Yuli Wei,Cheng Yang,Honggang Zhou,Xiaoping Li,Yunyao Cui,Zeping Li

doi:10.3389/fphar.2021.639574

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.

Highlights

Idiopathic pulmonary fibrosis is a progressive, fatal and age-associated disease, and the average survival time of IPF patients is only 2–5 years after diagnosis (Directors and Committie, 2000; Thannickal et al, 2004; Mora et al, 2017)
We demonstrated that Ellagic acid could alleviate BLM-induced pulmonary fibrosis in mice mainly by inhibiting fibroblast activation and inducing myofibroblast autophagy and apoptosis, and its main mechanism is regulating the Wnt pathway
We further explored whether Ellagic acid could decrease Wnt3a-induced myofibroblast activation and extracellular matrix (ECM) production and its underlying mechanism

Summary

Introduction

Idiopathic pulmonary fibrosis is a progressive, fatal and age-associated disease, and the average survival time of IPF patients is only 2–5 years after diagnosis (Directors and Committie, 2000; Thannickal et al, 2004; Mora et al, 2017). Ellagic Acid Attenuates Pulmonary Fibrosis understood, many researchers believe that myofibroblast activation, autophagy and apoptosis are essential factors in fibrotic progression (Wynn, 2011). Wnt signaling plays an essential role in fibrotic disease, and inhibiting this pathway could suppress fibrotic progression (Distler et al, 2019). In lung epithelial cells and fibroblasts, β-catenin is overexpressed under fibrotic conditions (Baarsma and Konigshoff, 2017). Many studies have revealed that Wnt ligands induce fibroblast activation and collagen synthesis and that blocking Wnt/β-catenin signaling attenuates BLM-induced pulmonary fibrosis (Konigshoff et al, 2008). Inhibiting fibroblast activation and promoting myofibroblast apoptosis could attenuate pulmonary fibrosis by suppressing Wnt/β-catenin signaling

Methods

Results

Conclusion