Integration of bioinformatics analysis and experimental verification reveals the role of neutrophil extracellular traps in silica nanoparticles-induced lung injury

BACKGROUND: Silica nanoparticles (SiNPs) are extensively produced and utilized, leading to regular human exposure in both living environmental and occupational settings. Numerous studies have confirmed the detrimental effects of SiNPs on respiratory health. Neutrophil extracellular traps (NETs), web-like networks of DNA, histones, and antimicrobial proteins that neutrophils release to trap and kill pathogens, are implicated in development of some acute and chronic lung diseases. Nevertheless, the specific role of NETs in the adverse pulmonary effects of SiNPs has not been described. METHODS: Male C57BL/6 mice received intratracheal instillation of 80 nm SiNPs at 3.0 and 6.0 mg/kg body weight (bw), once weekly for 12 weeks, to simulate actual occupational exposure scenarios. Combined with bioinformatics analysis, this exploratory study investigated SiNPs-induced lung injury and the impact on metrics related to NETs. Subsequently, DNase I was used to explore the mitigating effect and mechanisms of promoting NETs degradation on SiNPs-induced lung injury. The DNase I was administered at a dose of 300 U per mouse via intraperitoneal injection, three times a week for 12 weeks. RESULTS: Exposure to SiNPs induced pulmonary injury in C57BL/6 mice. Results of bioinformatic analyses and molecular bioassay techniques revealed that NETs, integrins αLβ2 and αMβ2, CD44, TGF-β and cytokines participate in SiNPs-induced lung injury. Targeted inhibition of NETs via DNase I attenuated the overexpression of integrins, CD44 and TGF-β, thereby mitigating SiNPs-induced lung injury. CONCLUSION: Exposure to SiNPs may cause pulmonary inflammation and fibrotic injury through NETs/integrins/TGF-β and NETs/cytokines/CD44 signaling pathways. Targeting NETs degradation may offer a novel therapeutic target for SiNPs-induced lung injury and provide a potential therapeutic avenue for inflammatory and fibrotic related diseases.