Inhibition of cGAS ameliorates acute lung injury triggered by zinc oxide nanoparticles

Purpose: Zinc oxide nanoparticles (ZnONPs) have been widely used in various industrial and biomedical fields. Occupational or accidental inhalation exposure to ZnONPs might lead to acute lung injury (ALI). Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are critical for the initiation and expansion of inflammation and contribute to tissue injury; however, the role and mechanism of the cGAS-STING pathway in ALI-induced by ZnONPs are unclear.Methods: Male C57BL/6 J mice were intratracheally injected with ZnONPs (0.6 mg/kg) or mock. The mice were euthanized and the degree of lung injury was determined 3 days after the instillation of ZnONPs. The BEAS-2B cell line was used as a cell model to investigate the cytotoxicity of ZnONPs in vitro.Results: We found that ZnONPs inhalation induced ALI in mice, manifested by exacerbated lung pathological changes, mitochondrial damage, oxidative stress and inflammation. Interestingly, cGAS and STING were acti-vated in the lung tissues of the mice and BEAS-2B lung epithelial cells treated with ZnONPs. More importantly, we illustrated that the cGAS inhibitor RU.521 inhibited the activation of the cGAS-STING pathway, further decreased oxidative stress and inflammation, and led to ameliorated lung injury in mice treated with ZnONPs.Conclusion: This study demonstrated that ZnONPs trigger the activation of the cGAS-STING pathway, which plays an important role in ZnONPs-induced ALI. Inhibition of cGAS with RU.521 mitigates the oxidative stress induced by ZnONPs, suggesting that targeting the cGAS-STING pathway may be a feasible strategy to ameliorate the pulmonary injury caused by nanoparticles.