Metformin attenuates silica-induced pulmonary fibrosis via AMPK signaling

Demin Cheng,Dongyu Ma,Lei Han,Guanru Li,Siyun Zhou,Qi Xu,Chunhui Ni,Yue Wang,Wenqing Sun,Yi Liu

doi:10.1186/s12967-021-03036-5

Abstract

BackgroundSilicosis 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.MethodsThe 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.ResultsAt 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.ConclusionsIn this study, we identified that metformin might be a potential drug for silicosis treatment.

Highlights

Silicosis is one of the most common occupational pneumoconiosis directly caused by exposure to respirable silica-based particles, which leads to an inflammatory cascade, progressive lung fibrosis, and devastated respiratory failure [1]
We evaluated the anti-fibrotic effects of metformin in the silica-induced lung fibrosis model at different stages to illustrate the underlying mechanisms in different cell types, including pulmonary epithelial cells, macrophages, and fibroblasts
Metformin attenuates Silicon dioxide (SiO2)‐induced lung fibrosis in vivo To elucidate whether metformin has a potential role in silica-induced pulmonary fibrosis, we established an intervention model by giving 100 or 300 mg/kg metformin to mice after silica-instillation for 28 days

Summary

Introduction

Silicosis is one of the most common occupational pneumoconiosis directly caused by exposure to respirable silica-based particles, which leads to an inflammatory cascade, progressive lung fibrosis, and devastated respiratory failure [1]. Macrophages play a crucial role in the progression of pulmonary fibrosis by triggering the inflammation cascade response and differentiating into a profibrotic phenotype [14, 15]. Silica damages the epithelial cell and activates the macrophage to cause an inflammatory microenvironment in the lung, which promotes adaptive immunity, fibroblast proliferation and migration, extracellular matrix secretion and collagen deposition, eventually leading to abnormal lung tissue remodeling and obstructive air exchange, even death [16, 17]. Suppression of the EMT process, inflammatory cascade response and fibroblast activation represent a visible approach for the amelioration of pulmonary fibrosis. We sought to investigate the role of metformin in silica-induced lung fibrosis

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Results

Discussion

Conclusion