Anti-infection effects of heparin on SARS-CoV-2 in a diabetic mouse model  

作　　者：Zhongyun Zhang Ning Zhang Xuancheng Lu Min Zhou Xiaoxiang Yan Weiqiong Gu Jingru Yang Qin Zhang Cheng Zhang Yuhuan Gong Mingjun Jia Xiaoyu Zhang Peng Ning Mei Liu Xiaoyan Li Xiaomeng Shi Wenjun Liu George FGao Guang Ning Jiqiu Wang Yuhai Bi 

机构地区：[1]Department of Endocrinology and Metabolism,Shanghai Institute of Endocrine and Metabolic Diseases,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [2]Shanghai National Clinical Research Center for Metabolic Diseases,Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China,Shanghai National Center for Translational Medicine,Shanghai 200025,China [3]CAS Key Laboratory of Pathogen Microbiology and Immunology,Institute of Microbiology,Center for Influenza Research and Early-warning(CASCIRE),CAS-TWAS Center of Excellence for Emerging Infectious Diseases(CEEID),Chinese Academy of Sciences,Beijing 100101,China [4]Laboratory Animal Center,Chinese Center for Disease Control and Prevention(China CDC),Beijing 102206,China [5]Department of Respiratory and Critical Care Medicine,Institute of Respiratory Diseases,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [6]Department of Cardiology,Institute of Cardiovascular Diseases,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [7]School of Laboratory Medicine and Life Sciences,Wenzhou Medical University,Wenzhou,Zhejiang 325000,China [8]University of Chinese Academy of Sciences,Beijing 100049,China

出　　处：《Zoological Research》2023年第6期1003-1014,共12页动物学研究（英文）

基　　金：supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) (XDB29010102);National Natural Science Foundation of China (NSFC) (91957124,82161148010,32041010);Self-supporting Program of Guangzhou Laboratory (SRPG22-001);National Science and Technology Infrastructure of China (National Pathogen Resource Center-NPRC-32);Management Strategy of the Tertiary Prevention and Treatment of Diabetes Based on DIP system (supported by China Health Promotion Foundation);supported by the Youth Innovation Promotion Association of CAS (Y2021034);Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202208)。

摘　　要：Severe acute respiratory syndrome coronavirus 2(SARSCo V-2)infection can result in more severe syndromes and poorer outcomes in patients with diabetes and obesity.However,the precise mechanisms responsible for the combined impact of coronavirus disease 2019(COVID-19)and diabetes have not yet been elucidated,and effective treatment options for SARS-Co V-2-infected diabetic patients remain limited.To investigate the disease pathogenesis,K18-h ACE2 transgenic(h ACE2^(Tg))mice with a leptin receptor deficiency(h ACE2-Lepr^(-/-))and high-fat diet(h ACE2-HFD)background were generated.The two mouse models were intranasally infected with a 5×10^(5) median tissue culture infectious dose(TCID_(50))of SARSCo V-2,with serum and lung tissue samples collected at 3days post-infection.The h ACE2-Lepr^(-/-)mice were then administered a combination of low-molecular-weight heparin(LMWH)(1 mg/kg or 5 mg/kg)and insulin via subcutaneous injection prior to intranasal infection with1×10^(4) TCID_(50)of SARS-Co V-2.Daily drug administration continued until the euthanasia of the mice.Analyses of viral RNA loads,histopathological changes in lung tissue,and inflammation factors were conducted.Results demonstrated similar SARS-Co V-2 susceptibility in h ACE2^(Tg)mice under both lean(chow diet)and obese(HFD)conditions.However,compared to the h ACE2-Lepr^(+/+)mice,h ACE2-Lepr^(-/-)mice exhibited more severe lung injury,enhanced expression of inflammatory cytokines and hypoxia-inducible factor-1α(HIF-1α),and increased apoptosis.Moreover,combined LMWH and insulin treatment effectively reduced disease progression and severity,attenuated lung pathological changes,and mitigated inflammatory responses.In conclusion,preexisting diabetes can lead to more severe lung damage upon SARS-Co V-2 infection,and LMWH may be a valuable therapeutic approach for managing COVID-19patients with diabetes.

关 键 词：SARS-CoV-2 DIABETES Mouse model HEPARIN Antiviral therapy 

分 类 号：R587.1[医药卫生—内分泌] R511[医药卫生—内科学] R-332[医药卫生—临床医学]