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

作者全名："Jiang, Ziqi; Jiang, Yu; Fan, Jingchuan; Zhang, Jun; Xu, Ge; Fan, Yinzhen; Zhang, Liyu; Qin, Xia; Jiang, Xuejun; Mao, Lejiao; Liu, Gang; Chen, Chengzhi; Zou, Zhen"

作者地址："[Jiang, Ziqi; Zhang, Jun; Xu, Ge; Mao, Lejiao; Zou, Zhen] Chongqing Med Univ, Inst Life Sci, Mol Biol Lab Resp Dis, Chongqing 400016, Peoples R China; [Jiang, Yu] Chongqing Med Univ, Univ Town Hosp, Dept Resp Med, Chongqing 401331, Peoples R China; [Fan, Jingchuan; Zhang, Liyu] Chongqing Med Univ, Sch Publ Hlth, Dept Hlth Lab Technol, Chongqing 400016, Peoples R China; [Qin, Xia] Chongqing Med Univ, Affiliated Hosp 1, Dept Pharm, Chongqing 400016, Peoples R China; [Jiang, Xuejun] Chongqing Med Univ, Ctr Expt Teaching Publ Hlth, Expt Teaching & Management Ctr, Chongqing, Peoples R China; [Liu, Gang] Chongqing Med Univ, Univ Town Hosp, Dept Emergency, Chongqing 401331, Peoples R China; [Chen, Chengzhi] Chongqing Med Univ, Sch Publ Hlth, Dept Occupat & Environm Hlth, Chongqing 400016, Peoples R China; [Chen, Chengzhi; Zou, Zhen] Chongqing Med Univ, Res Ctr Environm & Human Hlth, Sch Publ Hlth, Chongqing 400016, Peoples R China"

通信作者："Zou, Z (通讯作者)，Chongqing Med Univ, Inst Life Sci, Mol Biol Lab Resp Dis, Chongqing 400016, Peoples R China.; Liu, G (通讯作者)，Chongqing Med Univ, Univ Town Hosp, Dept Emergency, Chongqing 401331, Peoples R China.; Chen, CZ (通讯作者)，Chongqing Med Univ, Sch Publ Hlth, Dept Occupat & Environm Hlth, Chongqing 400016, Peoples R China."

来源：TOXICOLOGY LETTERS

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000890882600004

JCR分区：Q2

影响因子：2.9

年份：2023

卷号：373

期号：　

开始页：62

结束页：75

文献类型：Article

关键词：Zinc oxide nanoparticles; Acute lung injury; cGAS; Inflammation; RU; 521

摘要："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."

基金机构："Chongqing Talents: Exceptional Young Talents Project [CQYC2020058650]; National Natural Science Foundation of China [81903358]; Natural Science Foundation of Chongqing [cstc2021ycjh-bgzxm0105, cstc2020jcyj-msxmX0155, cstc2021jcyj-msxmX0141, cstc2020jcyj-msxmX0359]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJCXZD2020020]; Future Medical Youth Innovation Program of Chongqing Medical University [W0038]"

基金资助正文："Funding This work is supported by Chongqing Talents: Exceptional Young Talents Project (CQYC2020058650) , the National Natural Science Foundation of China (81903358) , the Natural Science Foundation of Chongqing (cstc2021ycjh-bgzxm0105, cstc2020jcyj-msxmX0155, cstc2021jcyj-msxmX0141 and cstc2020jcyj-msxmX0359) , the Science and Technology Research Program of Chongqing Municipal Education Commission (KJCXZD2020020) ,the Future Medical Youth Innovation Program of Chongqing Medical University (W0038) ."