期刊
EBIOMEDICINE
卷 67, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ebiom.2021.103382
关键词
COVID-19; Thrombosis; FXII; NETs; Pulmonary thrombo-inflammation
资金
- European Union [840189]
- Werner Otto Medical Foundation Hamburg [8/95]
- German Research Foundation (DFG) [FR 4239/1-1]
- DFG [A11/SFB877, B08/SFB841, P06/KFO306]
- Marie Curie Actions (MSCA) [840189] Funding Source: Marie Curie Actions (MSCA)
The study shows that increased expression and activity of FXII are found in lung tissues of COVID-19 patients, and NET accumulation leads to FXII contact activation. Additionally, insufficient DNase contributes to NETs accumulation, exacerbating FXII activation.
Background: Coagulopathy and inflammation are hallmarks of Coronavirus disease 2019 (COVID-19) and are associated with increased mortality. Clinical and experimental data have revealed a role for neutrophil extracellular traps (NETs) in COVID-19 disease. The mechanisms that drive thrombo-inflammation in COVID-19 are poorly understood. Methods: We performed proteomic analysis and immunostaining of postmortem lung tissues from COVID-19 patients and patients with other lung pathologies. We further compared coagulation factor XII (FXII) and DNase activities in plasma samples from COVID-19 patients and healthy control donors and determined NET-induced FXII activation using a chromogenic substrate assay. Findings: FXII expression and activity were increased in the lung parenchyma, within the pulmonary vasculature and in fibrin-rich alveolar spaces of postmortem lung tissues from COVID-19 patients. In agreement with this, plasmaaac acafajfoeFXII activation (FXIIa) was increased in samples from COVID-19 patients. Furthermore, FXIIa colocalized with NETs in COVID-19 lung tissue indicating that NETs accumulation leads to FXII contact activation in COVID-19. We further showed that an accumulation of NETs is partially due to impaired NET clearance by extracellular DNases as DNase substitution improved NET dissolution and reduced FXII activation in vitro. Interpretation: Collectively, our study supports that the NET/FXII axis contributes to the pathogenic chain of procoagulant and proinflammatory responses in COVID-19. Targeting both NETs and FXIIa may offer a potential novel therapeutic strategy. (C) 2021 The Authors. Published by Elsevier B.V.
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