Abstract
Background. 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.
Methods. Neutrophils were isolated from healthy volunteers (n=9) and hospitalised patients with COVID-19 at the acute stage (n=39) and again at 3–4 months post-acute sampling (n=7). NETosis was measured by SYTOX green assays.
Results. 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-acute sampling) 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.
Conclusion. 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.
Footnotes
This manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.
Conflict of interest: Rebecca Dowey has nothing to disclose.
Conflict of interest: Joby Cole has nothing to disclose.
Conflict of interest: A. A. Roger Thompson has nothing to disclose.
Conflict of interest: Rebecca C. Hull has nothing to disclose.
Conflict of interest: Chenghao Huang has nothing to disclose.
Conflict of interest: Jacob Whatmore has nothing to disclose.
Conflict of interest: Ahmed Iqbal has nothing to disclose.
Conflict of interest: Kirsty L. Bradley has nothing to disclose.
Conflict of interest: Joanne McKenzie has nothing to disclose.
Conflict of interest: Allan Lawrie has nothing to disclose.
Conflict of interest: Alison M. Condliffe has nothing to disclose.
Conflict of interest: Endre Kiss-Toth has nothing to disclose.
Conflict of interest: Ian Sabroe has nothing to disclose.
Conflict of interest: Lynne R. Prince has nothing to disclose.
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- Received October 20, 2021.
- Accepted January 12, 2022.
- Copyright ©The authors 2022
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