Metformin attenuates silica-induced pulmonary fibrosis via AMPK signaling

Abstract

Background Silicosis is one of the most common occupational pulmonary fibrosis caused by respirable silica-based particle exposure, with no ideal drugs at present. Metformin, a commonly used biguanide antidiabetic agent, could activate AMP-activated protein kinase (AMPK) to exert its pharmacological action. Therefore, we sought to investigate the role of metformin in silica-induced lung fibrosis. Methods The anti-fibrotic role of metformin was assessed in 50 mg/kg silica-induced lung fibrosis model. Silicon dioxide (SiO2)-stimulated lung epithelial cells/macrophages and transforming growth factor-beta 1 (TGF-β1)-induced differentiated lung fibroblasts were used for in vitro models. Results At the concentration of 300 mg/kg in the mouse model, metformin significantly reduced lung inflammation and fibrosis in SiO2-instilled mice at the early and late fibrotic stages. Besides, metformin (range 2–10 mM) reversed SiO2-induced cell toxicity, oxidative stress, and epithelial-mesenchymal transition process in epithelial cells (A549 and HBE), inhibited inflammation response in macrophages (THP-1), and alleviated TGF-β1-stimulated fibroblast activation in lung fibroblasts (MRC-5) via an AMPK-dependent pathway. Conclusions In this study, we identified that metformin might be a potential drug for silicosis treatment.

Transcriptome‐wide association study identifies PSMB9 as a susceptibility gene for coal workers' pneumoconiosis

“…The PSMB9 mRNA expression level was then measured via qRT‐PCR. HBE and A549 cells were exposed to different concentrations of silica (50, 100, 150, 200, and 250 μg/mL) for 12 and 24 h based on our previous studies on the cytotoxicity of silica in these lung epithelial cells 37,42 . Our results showed that PSMB9 mRNA expression was remarkably down‐regulated in both HBE and A549 cells with silica exposure, while no alteration of PSMB9 mRNA was observed in TGF‐β1‐treated MRC‐5 cells (Figure 4A, B and Supplementary file Figure S2).…”

“…HBE and A549 cells were exposed to different concentrations of silica (50,100,150,200, and 250 μg/mL) for 12 and 24 h based on our previous studies on the cytotoxicity of silica in these lung epithelial cells. 37,42 Our results showed that PSMB9 mRNA expression was remarkably down-regulated in both HBE and A549 cells with silica exposure, while no alteration of PSMB9 mRNA was observed in TGF-β1-treated MRC-5 cells (Figure 4A, B and Supplementary file Figure S2). The immunofluorescent staining results further confirmed that the protein level of PSMB9, which also named LMP2, was markedly decreased in HBE and A549 cells treated with silica (Figure 4C).…”

Metformin Alleviates LPS-Induced Acute Lung Injury by Regulating the SIRT1/NF-κB/NLRP3 Pathway and Inhibiting Endothelial Cell Pyroptosis

“…Unfettered pyroptosis can induce injury of multiple tissues, including ALI (Hou et al, 2018;Zeng et al, 2019); thus, targeting caspasemediated pyroptosis in specific cell types, such as macrophages , endothelial cells (Cheng et al, 2017), and epithelial cells (Zhang et al, 2018), may be a potential therapeutic strategy to alleviate inflammatory lung damage and organ failure, without degradation of the host defense barrier. Although the protective effects of metformin against lung injury have been well-demonstrated in various models (Tsaknis et al, 2012;Chen et al, 2015;Wu et al, 2018;Cheng et al, 2021), its protective effect against pulmonary ECs injury has not yet been reported. ECs line the surface of lung vasculature; thus, they are the first point of contact for pathogens and bacterial toxins and also the first point to respond to them.…”

Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: A preclinical systematic review and meta-analysis

“…In addition, the doses administered were pre-classified based on the inclusion of experiments to facilitate further subgroup analysis. The doses of administered MET were divided into three groups (0 < low-dose group <150 mg/kg, 150 mg/kg ≤ medium-dose group <300 mg/kg, and 300 mg/kg ≤ high-dose group ≤500 mg/kg) according to previous studies ( Gamad et al, 2018 ; Wu, 2018 ; Hao et al, 2019 ; Li et al, 2021a ; Li et al, 2021b ; Cheng et al, 2021 ).…”

“…Elevated E-cadherin (E-Cad) levels decrease α-SMA and vimentin and inhibit the epithelial–mesenchymal transition (EMT) process ( Li et al, 2021b ). The anti-PF effect of MET involves the inhibition of reactive oxygen species (ROS) and lipid peroxidation product malondialdehyde (MDA), which catalyzes the expression of antioxidant proteins to inhibit intracellular oxidative stress and other pathways ( Cheng et al, 2021 ).…”