Metformin alleviates crystalline silica-induced pulmonary fibrosis by remodeling endothelial cells to mesenchymal transition via autophagy signaling

Ecotoxicol Environ Saf. 2022 Oct 15:245:114100. doi: 10.1016/j.ecoenv.2022.114100. Epub 2022 Sep 22.

Abstract

Silicosis is a severe progressive lung disease without effective treatment methods. Previous evidence has demonstrated that endothelial cell to mesenchymal transition (EndoMT) plays an essential role in pulmonary fibrosis, and pulmonary fibrosis is associated with dysregulation of autophagy, while the relationship between autophagy and EndoMT has not yet been adequately studied. Herein, we established a mouse model of silicosis, and we found that the pharmacological induction of the AMPK/mTOR-dependent pathway using 100 mg/kg Metformin (Met) enhanced autophagy in vivo, and results of the Western blot showed that autophagy-related proteins, LC3 II/I ratio, and Beclin-1 increased while p62 decreased. In addition, Met treatment attenuated silica-induced pulmonary inflammation and decreased collagen deposition by suppressing EndoMT, and the proliferation of human umbilical vein endothelial cells (HUVECs) was also inhibited. Notably, the tube forming assay showed that Met also protected the vascular endothelial cells from silica-induced morphological damage. In conclusion, Met can alleviate inflammatory response and collagen deposition in the process of pulmonary fibrosis induced by silica via suppressing EndoMT through the AMPK/mTOR signaling pathway.

Keywords: Autophagy; Endothelial cell to mesenchymal transition; Metformin; Silicosis.

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Autophagy
  • Autophagy-Related Proteins / pharmacology
  • Beclin-1
  • Collagen
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Metformin* / pharmacology
  • Mice
  • Pulmonary Fibrosis* / chemically induced
  • Pulmonary Fibrosis* / drug therapy
  • Signal Transduction
  • Silicon Dioxide / toxicity
  • Silicosis* / drug therapy
  • TOR Serine-Threonine Kinases

Substances

  • Autophagy-Related Proteins
  • Beclin-1
  • Silicon Dioxide
  • Collagen
  • Metformin
  • TOR Serine-Threonine Kinases
  • AMP-Activated Protein Kinases