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-cy...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.展开更多
Influenza virus (IAV)infection is a major cause of severe respiratory illness that affects almost every country in the world.IAV infections result in respiratory illness and even acute lung injury and death,but the un...Influenza virus (IAV)infection is a major cause of severe respiratory illness that affects almost every country in the world.IAV infections result in respiratory illness and even acute lung injury and death,but the underlying mechanisms responsible for IAV pathogenesis have not yet been fully elucidated.In this study,the basic fibroblast growth factor 2 (FGF2)level was markedly increased in H1N1 virus-infected humans and mice.FGF2,which is predominately derived from epithelial cells,recruits and activates neutrophils via the FGFR2-PI3K-AKT-NFKB signaling pathway.FGF2 depletion or knockout exacerbated influenzaassociated disease by impairing neutrophil recruitment and activation.More importantly,administration of the recombinant FGF2 protein significantly aUeviated the severity of IAV-induced lung injury and promoted the survival of IAV-infected mice.Based on the results from experiments in which neutrophils were depleted and adoptively transferred,FGF2 protected mice against IAV , infection by recruiting neutrophils.Thus,FGF2 plays a critical role in preventing IAV-induced lung injury,and FGF2 is a promising potential therapeutic target during IAV infection.展开更多
基金supported by Major Program of National Natural Science Foundation of China (82192910)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202009 and ZYYCXTD-D-202207)。
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).
文摘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.
基金funding from the National High Technology Research and Development Program of China (SS2015AA020924)the National Natural Science Foundation of China (81771700)+2 种基金the Ministry of Science and Technology of China (2013ZXI0004003 and SS2012AA020905)the National Major Research and Development Program (2016YFA0502203 and 2017YFC1200800)P.Y.was supported by the Beijing Nova Program (Z141107001814054).
文摘Influenza virus (IAV)infection is a major cause of severe respiratory illness that affects almost every country in the world.IAV infections result in respiratory illness and even acute lung injury and death,but the underlying mechanisms responsible for IAV pathogenesis have not yet been fully elucidated.In this study,the basic fibroblast growth factor 2 (FGF2)level was markedly increased in H1N1 virus-infected humans and mice.FGF2,which is predominately derived from epithelial cells,recruits and activates neutrophils via the FGFR2-PI3K-AKT-NFKB signaling pathway.FGF2 depletion or knockout exacerbated influenzaassociated disease by impairing neutrophil recruitment and activation.More importantly,administration of the recombinant FGF2 protein significantly aUeviated the severity of IAV-induced lung injury and promoted the survival of IAV-infected mice.Based on the results from experiments in which neutrophils were depleted and adoptively transferred,FGF2 protected mice against IAV , infection by recruiting neutrophils.Thus,FGF2 plays a critical role in preventing IAV-induced lung injury,and FGF2 is a promising potential therapeutic target during IAV infection.
