Danshensu alleviates pseudo-typed SARS-CoV-2 induced mouse acute lung inflammation

被引：29

作者：

Wang, Wei ^{[1
]}

Li, Sha-sha ^{[1
]}

Xu, Xin-feng ^{[1
]}

Yang, Chan ^{[1
]}

Niu, Xiao-ge ^{[1
]}

Yin, Shu-xian ^{[2
]}

Pan, Xiao-yan ^{[3
]}

Xu, Wei ^{[1
]}

Hu, Guo-dong ^{[2
]}

Wang, Chan ^{[1
]}

Liu, Shu-wen ^{[1
,4
]}

机构：

[1] Southern Med Univ, Sch Pharmaceut Sci, Guangdong Prov Key Lab New Drug Screening, Guangzhou 510515, Peoples R China

[2] Southern Med Univ, Nanfang Hosp, Dept Resp & Crit Care Med, Guangzhou 510515, Peoples R China

[3] Chinese Acad Sci, Ctr Biosafety Megasci, State Key Lab Virol, Wuhan Inst Virol, Wuhan 430071, Peoples R China

[4] Southern Med Univ, Guangdong Prov Inst Nephrol, State Key Lab Organ Failure Res, Guangzhou 510515, Peoples R China

来源：

ACTA PHARMACOLOGICA SINICA | 2022年 / 43卷 / 04期

基金：

中国国家自然科学基金;

关键词：

Danshensu; SARS-CoV-2; spike protein; acute lung inflammation; inflammatory cytokines; NF-KAPPA-B; PNEUMONIA; INJURY; MECHANISMS; PATHWAYS; MODEL; RATS; MICE; ACE2;

D O I：

10.1038/s41401-021-00714-4

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can induce acute inflammatory response like acute lung inflammation (ALI) or acute respiratory distress syndrome, leading to severe progression and mortality. Therapeutics for treatment of SARS-CoV-2-triggered respiratory inflammation are urgent to be discovered. Our previous study shows that Salvianolic acid C potently inhibits SARS-CoV-2 infection. In this study, we investigated the antiviral effects of a Salvia miltiorrhiza compound, Danshensu, in vitro and in vivo, including the mechanism of S protein-mediated virus attachment and entry into target cells. In authentic and pseudo-typed virus assays in vitro, Danshensu displayed a potent antiviral activity against SARS-CoV-2 with EC50 of 0.97 mu M, and potently inhibited the entry of SARS-CoV-2 S protein-pseudo-typed virus (SARS-CoV-2 S) into ACE2-overexpressed HEK-293T cells (IC50 = 0.31 mu M) and Vero-E6 cell (IC50 = 4.97 mu M). Mice received SARS-CoV-2 S via trachea to induce ALI, while the VSV-G treated mice served as controls. The mice were administered Danshensu (25, 50, 100 mg/kg, i.v., once) or Danshensu (25, 50, 100 mg center dot kg(-1)center dot d(-1), oral administration, for 7 days) before SARS-CoV-2 S infection. We showed that SARS-CoV-2 S infection induced severe inflammatory cell infiltration, severely damaged lung tissue structure, highly expressed levels of inflammatory cytokines, and activated TLR4 and hyperphosphorylation of the NF-kappa B p65; the high expression of angiotensinogen (AGT) and low expression of ACE2 at the mRNA level in the lung tissue were also observed. Both oral and intravenous pretreatment with Danshensu dose-dependently alleviated the pathological alterations in mice infected with SARS-CoV-2 S. This study not only establishes a mouse model of pseudo-typed SARS-CoV-2 (SARS-CoV-2 S) induced ALI, but also demonstrates that Danshensu is a potential treatment for COVID-19 patients to inhibit the lung inflammatory response.

引用

页码：771 / 780

页数：10

共 63 条

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