2. Academic Validation
  3. VX-765 attenuates silica-induced lung inflammatory injury and fibrosis by modulating alveolar macrophages pyroptosis in mice

VX-765 attenuates silica-induced lung inflammatory injury and fibrosis by modulating alveolar macrophages pyroptosis in mice

  • Ecotoxicol Environ Saf. 2022 Dec 9;249:114359. doi: 10.1016/j.ecoenv.2022.114359.
Huihui Tao 1,  Hui Zhao 1,  Aowei Mo 2,  Luocheng Shao 2,  Deyong Ge 3,  Jiale Liu 2,  Wenjian Hu 2,  Keyi Xu 3,  Qianqian Ma 3,  Wenfeng Wang 4,  Wenyang Wang 3,  Hangbing Cao 3,  Min Mu 3,  Xinrong Tao 5,  Jianhua Wang 6
Affiliations

Affiliations

  • 1 Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, China; Key Laboratory of Industrial Dust Prevention and Control & Occupational Health and Safety, Ministry of Education, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Anhui University of Science & Technology, Huainan, China; State Key Laboratory of Cellular Stress Biology, Xiamen University, China.
  • 2 School of Medicine, Anhui University of Science & Technology, Huainan, China.
  • 3 Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, China; Key Laboratory of Industrial Dust Prevention and Control & Occupational Health and Safety, Ministry of Education, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Anhui University of Science & Technology, Huainan, China.
  • 4 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 5 Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, China; Key Laboratory of Industrial Dust Prevention and Control & Occupational Health and Safety, Ministry of Education, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Anhui University of Science & Technology, Huainan, China. Electronic address: [email protected].
  • 6 Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan, China; Key Laboratory of Industrial Dust Prevention and Control & Occupational Health and Safety, Ministry of Education, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Anhui University of Science & Technology, Huainan, China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China. Electronic address: [email protected].
PMID: 36508797 DOI: 10.1016/j.ecoenv.2022.114359
Abstract

Silicosis is a diffuse fibrotic lung disease in which excessive inflammatory responses are triggered by silica exposure. Pyroptosis, a pro-inflammatory mode of programmed cell death, is mediated by gasdermin and may play a pivotal role in the development of silicosis. The Caspase-1 inhibitor, VX-765, was used in vivo and in vitro to investigate the effects of silica-induced early inflammatory injury and later lung fibrosis. Our findings show that VX-765 reduces inflammatory lung injury by inhibiting silica-induced Pyroptosis of alveolar macrophages in a silicosis mouse model. VX-765 limits the infiltration of inflammatory M1 alveolar macrophages, decreasing expression of inflammatory cytokines, including IL-1β, TNF-α, IL-6, CCL2, and CCL3, and down-regulating endogenous DAMPs and inflammatory immune-related cell Pattern Recognition Receptors TLR4 and NLRP3. Furthermore, VX-765 alleviates fibrosis by down-regulating α-smooth muscle actin (α-SMA), collagen, and fibronectin. In this study, we illustrate that Alveolar macrophages Pyroptosis occur in the early stages of silicosis, and VX-765 can alleviate the development of silicosis by inhibiting the Pyroptosis signaling pathway. These results may provide new insight into the prevention and treatment of early-stage silicosis.

Keywords

Alveolar macrophages; Caspase-1; Pyroptosis; Silica exposure; Silicosis; VX-765.

Figures
Products