Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation.
Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation.
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DOI：
10.1016/j.ebiom.2021.103382
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发表时间：
2021-05
期刊：
影响因子：
11.1
通讯作者：
Frye M
中科院分区：
文献类型：
--
作者：
Englert H;Rangaswamy C;Deppermann C;Sperhake JP;Krisp C;Schreier D;Gordon E;Konrath S;Haddad M;Pula G;Mailer RK;Schlüter H;Kluge S;Langer F;Püschel K;Panousis K;Stavrou EX;Maas C;Renné T;Frye M
凝血病和炎症是2019冠状病毒病（COVID-19）的标志，并与死亡率增加有关。临床和实验数据揭示了中性粒细胞胞外陷阱（NET）在COVID-19疾病中的作用。人们对COVID-19中驱动血栓炎症的机制知之甚少。我们对COVID-19患者和其他肺部病变患者的死后肺组织进行了蛋白质组学分析和免疫染色。我们进一步比较了COVID-19患者和健康对照供体血浆样本中的凝血因子XII（FXII）和DNA酶活性，并使用显色底物测定法测定了NET诱导的FXII活化。在COVID-19患者的死后肺组织的肺实质、肺血管内和富含纤维蛋白的肺泡腔中，FXII表达和活性增加。与此一致，COVID-19患者的血浆acafajföeFXII激活（FXIIa）增加。此外，FXIIa与NET在COVID-19肺组织中共定位，表明NET积累导致COVID-19中的FXII接触活化。我们进一步表明，NET的积累部分是由于细胞外DNA酶的NET清除受损，因为DNA酶取代改善了NET溶解并降低了体外FXII活化。总的来说，我们的研究支持NET/FXII轴有助于COVID-19中促凝血和促炎反应的致病链。靶向NET和FXIIa可能提供潜在的新治疗策略。本研究得到了欧盟（840189）、汉堡Werner Otto医学基金会（8/95）和德国研究基金会（FR 4239/1-1、A11/SFB 877、B 08/SFB 841和P06/KFO 306）的支持。
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. 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. 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 acafajföeFXII 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. 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. This study was supported by the European Union (840189), the Werner Otto Medical Foundation Hamburg (8/95) and the German Research Foundation (FR4239/1-1, A11/SFB877, B08/SFB841 and P06/KFO306).
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DOI：
10.1056/nejmoa2022926
发表时间：
2020-11-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
RECOVERY Collaborative Group;Horby P;Mafham M;Linsell L;Bell JL;Staplin N;Emberson JR;Wiselka M;Ustianowski A;Elmahi E;Prudon B;Whitehouse T;Felton T;Williams J;Faccenda J;Underwood J;Baillie JK;Chappell LC;Faust SN;Jaki T;Jeffery K;Lim WS;Montgomery A;Rowan K;Tarning J;Watson JA;White NJ;Juszczak E;Haynes R;Landray MJ
通讯作者：
Landray MJ
影响因子：
16.6
作者：
Frye M;Taddei A;Dierkes C;Martinez-Corral I;Fielden M;Ortsäter H;Kazenwadel J;Calado DP;Ostergaard P;Salminen M;He L;Harvey NL;Kiefer F;Mäkinen T
通讯作者：
Mäkinen T
影响因子：
158.5
作者：
Ackermann, Maximilian;Verleden, Stijn E.;Jonigk, Danny
通讯作者：
Jonigk, Danny
影响因子：
2.1
作者：
Edler, Carolin;Schroeder, Ann Sophie;Sperhake, Jan-Peter
通讯作者：
Sperhake, Jan-Peter
影响因子：
20.3
作者：
Fuchs, Tobias A.;Hovinga, Johanna A. Kremer;Laemmle, Bernhard
通讯作者：
Laemmle, Bernhard