Epigallocatechin Gallate Relieved PM2.5-Induced Lung Fibrosis by Inhibiting Oxidative Damage and Epithelial-Mesenchymal Transition through AKT/mTOR Pathway

Abstract

Oxidative damage and epithelial-mesenchymal transition (EMT) are main pathological processes leading to the development of PM2.5-induced lung fibrosis. Epigallocatechin gallate (EG), a natural polyphenol extracted from green tea, possesses the ability to combat oxidative stress and inflammation. However, the potential roles of EG in PM2.5-induced lung fibrosis have not been reported yet. In the present study, we investigated whether EG could relieve PM2.5-induced lung injury and fibrosis in vivo and in vitro. To mimic PM2.5-induced lung fibrosis, C57/BL6 mice were intranasally instilled with PM2.5 suspension, and MLE-12 lung epithelial cells were stimulated with PM2.5 (100 μg/mL) in vitro. The results showed that intragastric administration of EG (20 mg/kg/d or 80 mg/kg/d for 8 weeks) significantly prevented lung injury, inflammation, and oxidative stress in PM2.5-induced mice, apart from inhibiting collagen deposition. Additionally, EG treatment also suppressed the activation of AKT/mTOR signaling pathway in lung tissues challenged with PM2.5. In vitro experiments further demonstrated that EG treatment could enhance cell viability in a concentration-dependent manner in PM2.5-treated MLE-12 lung epithelial cells. Also, the overexpression of constitutively active AKT could offset the inhibitory effects of EG on EMT and oxidative stress in PM2.5-treated MLE-12 lung epithelial cells. Finally, AKT overexpression also blocked the inhibitory effect of EG on the phosphorylation of mTOR in PM2.5-treated MLE-12 lung epithelial cells. In conclusion, EG could improve PM2.5-induced lung fibrosis by decreasing oxidative damage and EMT through AKT/mTOR pathway, which might be a potential candidate for the treatment of PM2.5-induced lung fibrosis.

Potential of Plant-Derived Compounds in Preventing and Reversing Organ Fibrosis and the Underlying Mechanisms

“…A number of studies have illustrated the anti-fibrotic effects of EGCG in the liver [ 77 ], kidney [ 78 ], lungs [ 79 ], heart [ 80 ] and other organs. Treatment with EGCG in isolated uterine fibroid or myometrial cells resulted in the reduction in mRNA or protein levels of critical fibrotic markers including fibronectin, collagen I, plasminogen activator inhibitor-1 (PAI-1), CTGF and α-SMA [ 81 ].…”

Particulate Matter-Induced Oxidative Stress – Recent Mechanistic Insights from In Vitro Studies

“…EMT is identified by a decrease in epithelial markers of tight junctions, such E-cadherin, and an increase in mesenchymal markers such as alpha smooth muscle actin (a-SMA) and vimentin. Several recent studies have reported changes in these markers following PM-exposure (Chen et al, 2020;Liu et al, 2022a;Pan et al, 2021;Saha et al, 2022;Wang et al, 2022d;Zhongyin et al, 2022), but only one clearly demonstrated the cascade of events, from ROS generation to NF-kB activation to EMT induction, using antioxidants and an NF-kB inhibitor (Chen et al, 2020). The transforming growth factor beta 1 (TGF-b1) is yet another important player in EMT-mediated airway remodeling induced by PM exposure.…”

“…Ephedrine (an alkaloid), (-)-epicatechin and biochanin A (flavonoids), and glycyrrhizin (a saponin) proved to have similar Nfr2 induction activity that helped bronchial and alveolar epithelial cells counteract the PM-induced cytotoxic effects (Shi et al, 2023;Tian et al, 2021;Wang et al, 2022a;Xue et al, 2021b). The green tea derived polyphenols gallocatechin gallate and epigallocatechin gallate have demonstrated their antioxidant activity to counteract PMinduced oxidative potential in vitro, possibly by inhibiting the protein kinase B/ mammalian target of rapamycin (Akt/mTOR) pathway, therefore alleviating oxidative stress and EMT induced by PM (Tanaka et al, 2022;Zhongyin et al, 2022). Treatment with antioxidants based on traditional Chinese and Northeast Asian medicine, such as Tiaobu Feishen formulae, effective-component compatibility of Bufei Yishen formula (ECC-BYF), and Citrus junos peel extracts have also shown to be effective in overcoming PM-induced oxidative stress (Haoran et al, 2020;Lee et al, 2022a;Li et al, 2021).…”