Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the PKC inhibitor ruboxistaurin
Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the PKC inhibitor ruboxistaurin
Abstract Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs have emerged as critical mediators of lung damage, inflammation and thrombosis in COVID-19 and other diseases, but there are no therapeutics to prevent or reduce NETs that are available to patients. Here, we show that neutrophils isolated from hospitalised patients with COVID-19 produce significantly more NETs in response to LPS compared to cells from healthy control subjects. A subset of patients were captured at follow-up clinics (3-4 month post-infection) and while LPS-induced NET formation is significantly lower at this time point, it remains elevated compared to healthy controls. LPS- and PMA-induced NETs were significantly inhibited by the protein kinase C (PKC) inhibitor ruboxistaurin. Ruboxistaurin-mediated inhibition of NETs in healthy neutrophils reduces NET-induced epithelial cell death. Our findings suggest ruboxistaurin could reduce proinflammatory and tissue-damaging consequences of neutrophils during disease, and since it has completed phase III trials for other indications without safety concerns, it is a promising and novel therapeutic strategy for COVID-19.
Bradley Kirsty L、McKenzie Joanne、Hull Rebecca C、Kiss-Toth Endre、Prince Lynne R、Dowey Rebecca、Lawrie Allan、Huang Chenghao、Thompson A A Roger、Iqbal Ahmed、Sabroe Ian、Condliffe Alison M、Whatmore Jacob、Cole Joby
Department of Infection, Immunity and Cardiovascular Disease, University of SheffieldDepartment of Infection, Immunity and Cardiovascular Disease, University of SheffieldDepartment of Infection, Immunity and Cardiovascular Disease, University of SheffieldDepartment of Infection, Immunity and Cardiovascular Disease, University of SheffieldDepartment of Infection, Immunity and Cardiovascular Disease, University of SheffieldDepartment of Infection, Immunity and Cardiovascular Disease, University of SheffieldDepartment of Infection, Immunity and Cardiovascular Disease, University of SheffieldFaculty of Medicine, Dentistry and Health, University of SheffieldDepartment of Infection, Immunity and Cardiovascular Disease, University of SheffieldSheffield Teaching Hospitals NHS Foundation Trust||Department of Oncology and Metabolism, University of SheffieldSheffield Teaching Hospitals NHS Foundation TrustDepartment of Infection, Immunity and Cardiovascular Disease, University of SheffieldFaculty of Medicine, Dentistry and Health, University of SheffieldDepartment of Infection, Immunity and Cardiovascular Disease, University of Sheffield||Sheffield Teaching Hospitals NHS Foundation Trust
医药卫生理论医学研究方法基础医学
NeutrophilCOVID-19NETosisRuboxistaurin
Bradley Kirsty L,McKenzie Joanne,Hull Rebecca C,Kiss-Toth Endre,Prince Lynne R,Dowey Rebecca,Lawrie Allan,Huang Chenghao,Thompson A A Roger,Iqbal Ahmed,Sabroe Ian,Condliffe Alison M,Whatmore Jacob,Cole Joby.Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the PKC inhibitor ruboxistaurin[EB/OL].(2025-03-28)[2025-05-04].https://www.medrxiv.org/content/10.1101/2021.08.24.21262336.点此复制
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