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

• Published in: Ecotoxicology and environmental safety Vol. 249; p. 114359
• Main Authors: Tao, Huihui, Zhao, Hui, Mo, Aowei, Shao, Luocheng, Ge, Deyong, Liu, Jiale, Hu, Wenjian, Xu, Keyi, Ma, Qianqian, Wang, Wenfeng, Wang, Wenyang, Cao, Hangbing, Mu, Min, Tao, Xinrong, Wang, Jianhua
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-01-2023; Elsevier
• Subjects: Alveolar macrophages; Animals; Caspase Inhibitors - pharmacology; Caspase Inhibitors - therapeutic use; Caspase-1; Lung Injury - chemically induced; Lung Injury - drug therapy; Lung Injury - pathology; Macrophages, Alveolar - drug effects; Mice; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - drug therapy; Pyroptosis; Pyroptosis - drug effects; Silica exposure; Silicon Dioxide - toxicity; Silicosis; Silicosis - drug therapy; VX-765; VX-765; PRRs; AMs; HMGB1; Caspase-1; DAMPs; α-SMA; LDH; CCL3; CCL2; NLRP3; CCK-8; Silicosis; SiO2; Pyroptosis; IL-1β; Alveolar macrophages; IL-6; PCD; NF-КB; Silica exposure; TNF-α; GSGMD; TLR4; ATP; ELISA
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2022.114359

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.
•VX-765 attenuates silica-induced macrophage pyroptosis by blocking caspase-1 activation.•VX-765 reduces immune inflammatory responses by inhibiting AMs pyroptosis early in silica exposure.•VX-765 ameliorates late pulmonary fibrosis induced by silica.