Inosine:A broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation  

作　　者：Ningning Wang Entao Li Huifang Deng Lanxin Yue Lei Zhou Rina Su Baokun He Chengcai Lai Gaofu Li Yuwei Gao Wei Zhou Yue Gao 

机构地区：[1]Department of Pharmaceutical Sciences,Beijing Institute of Radiation Medicine,Beijing,100850,China [2]Tianjin University of Traditional Chinese Medicine,Tianjin,301617,China [3]Changchun Veterinary Research Institute,Chinese Academy of Agricultural Sciences,Changchun,130122,China [4]College of Veterinary Medicine,Jilin Agricultural University,Changchun,130022,China [5]Department of Gastroenterology,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,200080,China

出　　处：《Journal of Pharmaceutical Analysis》2023年第1期11-23,共13页药物分析学报（英文版）

基　　金：from the Young Elite Scientists Sponsorship Program by CAST(Grant No.:2021-QNRC1-03);the National Key Research and Development Program of China(Grant No.:2020YFC0845400).

摘　　要：Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-induced cytokine storms constitute the primary cause of coronavirus disease 19(COVID-19)progression,severity,criticality,and death.Glucocorticoid and anti-cytokine therapies are frequently administered to treat COVID-19,but have limited clinical efficacy in severe and critical cases.Nevertheless,the weaknesses of these treatment modalities have prompted the development of anti-inflammatory therapy against this infection.We found that the broad-spectrum anti-inflammatory agent inosine downregulated proinflammatory interleukin(IL)-6,upregulated anti-inflammatory IL-10,and ameliorated acute inflammatory lung injury caused by multiple infectious agents.Inosine significantly improved survival in mice infected with SARS-CoV-2.It indirectly impeded TANK-binding kinase 1(TBK1)phosphorylation by binding stimulator of interferon genes(STING)and glycogen synthase kinase-3β(GSK3β),inhibited the activation and nuclear translocation of the downstream transcription factors interferon regulatory factor(IRF3)and nuclear factor kappa B(NF-κB),and downregulated IL-6 in the sera and lung tissues of mice infected with lipopolysaccharide(LPS),H1N1,or SARS-CoV-2.Thus,inosine administration is feasible for clinical anti-inflammatory therapy against severe and critical COVID-19.Moreover,targeting TBK1 is a promising strategy for inhibiting cytokine storms and mitigating acute inflammatory lung injury induced by SARS-CoV-2 and other infectious agents.

关 键 词：CYTOKINE stormInterleukin 6 (IL-6)InosineSARS-CoV-2TANK-binding kinase 1 (TBK1) 

分 类 号：R563.1[医药卫生—呼吸系统]