Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation

被引:71
作者
Englert, Hanna [1 ]
Rangaswamy, Chandini [1 ]
Deppermann, Carsten [1 ]
Sperhake, Jan-Peter [2 ]
Krisp, Christoph [1 ]
Schreier, Danny [1 ]
Gordon, Emma [3 ]
Konrath, Sandra [1 ]
Haddad, Munif [1 ]
Pula, Giordano [1 ]
Mailer, Reiner K. [1 ]
Schlueter, Hartmut [1 ]
Kluge, Stefan [4 ]
Langer, Florian [5 ]
Pueschel, Klaus [2 ]
Panousis, Kosta [6 ]
Stavrou, Evi X. [7 ,8 ]
Maas, Coen [9 ]
Renne, Thomas [1 ]
Frye, Maike [1 ]
机构
[1] Univ Med Ctr Hamburg Eppendorf, Inst Clin Chem & Lab Med, Hamburg, Germany
[2] Univ Med Ctr Hamburg Eppendorf, Dept Legal Med, Hamburg, Germany
[3] Univ Queensland, Inst Mol Biosci, Div Cell & Dev Biol, Brisbane, Qld, Australia
[4] Univ Med Ctr Hamburg Eppendorf, Dept Intens Care Med, Hamburg, Germany
[5] Univ Med Ctr Hamburg Eppendorf, Med Clin & Polyclin 2, Hamburg, Germany
[6] CSL Ltd, Inst BIO21, Parkville, Vic, Australia
[7] CWRU Sch Med, Div Hematol & Oncol, Dept Med, Cleveland, OH USA
[8] Louis Stokes Vet Adm Med Ctr, Hematol Oncol Sect, Dept Med, Cleveland, OH USA
[9] Univ Utrecht, Univ Med Ctr Utrecht, Dept Clin Chem & Haematol, Utrecht, Netherlands
关键词
COVID-19; Thrombosis; FXII; NETs; Pulmonary thrombo-inflammation; NEUTROPHILS; BRADYKININ; HEPARIN; GENERATION; SYSTEM; DNA;
D O I
10.1016/j.ebiom.2021.103382
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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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页数:9
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