ISRIB inhibits the senescence of type II pulmonary epithelial cells to alleviate pulmonary fibrosis induced by silica in mice

Ya-Qian Li; Xu-Liang An; Fu-Yu Jin; Yi-Fei Bai; Tian Li; Xin-Yu Yang; Shu-Peng Liu; Xue-Min Gao; Na Mao; Hong Xu; Wen-Chen Cai; Fang Yang

doi:10.1016/j.ecoenv.2023.115410

ISRIB inhibits the senescence of type II pulmonary epithelial cells to alleviate pulmonary fibrosis induced by silica in mice

Ecotoxicol Environ Saf. 2023 Oct 1:264:115410. doi: 10.1016/j.ecoenv.2023.115410. Epub 2023 Aug 28.

Authors

Ya-Qian Li¹, Xu-Liang An¹, Fu-Yu Jin¹, Yi-Fei Bai¹, Tian Li¹, Xin-Yu Yang¹, Shu-Peng Liu¹, Xue-Min Gao², Na Mao¹, Hong Xu³, Wen-Chen Cai⁴, Fang Yang⁵

Affiliations

¹ School of public and health, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, China.
² School of public and health, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, China; NHC Key Laboratory of Pneumoconiosis，Department of Pulmonary and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan, China.
³ School of public and health, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, China; Health Scicence Center, North China University of Science and Technology, Tangshan, China.
⁴ School of public and health, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, China. Electronic address: caiwenchen@ncst.edu.cn.
⁵ School of public and health, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, China. Electronic address: fangyang@ncst.edu.cn.

PMID: 37647802
DOI: 10.1016/j.ecoenv.2023.115410

Abstract

The role and mechanisms of integrated stress response inhibitor (ISRIB) on silicosis are still not well defined. In the present study, the effects of ISRIB on cellular senescence and pulmonary fibrosis in silicosis were evaluated by RNA sequencing, micro-computed tomography, pulmonary function assessment, histological examination, and Western blot analysis. The results showed that ISRIB significantly reduced the degree of pulmonary fibrosis in mice with silicosis and reduced the expression of type I collagen, fibronectin, α-smooth muscle actin, and transforming growth factor-β1. Both in vivo and in vitro results showed that ISRIB reversed the expression of senescence-related factors β-galactosidase, phosphor-ataxia telangiectasia mutated, phosphor-ataxia telangiectasia and Rad3-related protein, p-p53, p21, p16, and plasminogen activator inhibitor type 1. The aforementioned results were consistent with the sequencing results. These findings implied that ISRIB might reduce the degree of pulmonary fibrosis in mice with silicosis by inhibiting the cellular senescence of alveolar epithelial cell type II.

Keywords: AEC2; Fibrosis; ISRIB; Senescence; Silicosis.

MeSH terms

Alveolar Epithelial Cells
Animals
Ataxia Telangiectasia*
Mice
Pulmonary Fibrosis* / chemically induced
Silicon Dioxide / toxicity
Silicosis*
X-Ray Microtomography

Substances

Silicon Dioxide