Neutrophil extracellular traps promote deep vein thrombosis in mice
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Neutrophil extracellular traps promote deep vein thrombosis in mice. / Brill, A; Fuchs, T A; Savchenko, A S; Thomas, G M; Martinod, K; De Meyer, S F; Bhandari, A A; Wagner, Denisa D.
in: J THROMB HAEMOST, Jahrgang 10, Nr. 1, 01.01.2012, S. 136-44.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Neutrophil extracellular traps promote deep vein thrombosis in mice
AU - Brill, A
AU - Fuchs, T A
AU - Savchenko, A S
AU - Thomas, G M
AU - Martinod, K
AU - De Meyer, S F
AU - Bhandari, A A
AU - Wagner, Denisa D
PY - 2012/1/1
Y1 - 2012/1/1
N2 - BACKGROUND: Upon activation, neutrophils can release nuclear material known as neutrophil extracellular traps (NETs), which were initially described as a part of antimicrobial defense. Extracellular chromatin was recently reported to be prothrombotic in vitro and to accumulate in plasma and thrombi of baboons with experimental deep vein thrombosis (DVT).OBJECTIVE: To explore the source and role of extracellular chromatin in DVT.METHODS: We used an established murine model of DVT induced by flow restriction (stenosis) in the inferior vena cava (IVC).RESULTS: We demonstrate that the levels of extracellular DNA increase in plasma after 6 h IVC stenosis, compared with sham-operated mice. Immunohistochemical staining revealed the presence of Gr-1-positive neutrophils in both red (RBC-rich) and white (platelet-rich) parts of thrombi. Citrullinated histone H3 (CitH3), an element of NETs' structure, was present only in the red part of thrombi and was frequently associated with the Gr-1 antigen. Immunofluorescent staining of thrombi showed proximity of extracellular CitH3 and von Willebrand factor (VWF), a platelet adhesion molecule crucial for thrombus development in this model. Infusion of Deoxyribonuclease 1 (DNase 1) protected mice from DVT after 6 h and also 48 h IVC stenosis. Infusion of an unfractionated mixture of calf thymus histones increased plasma VWF and promoted DVT early after stenosis application.CONCLUSIONS: Extracellular chromatin, likely originating from neutrophils, is a structural part of a venous thrombus and both the DNA scaffold and histones appear to contribute to the pathogenesis of DVT in mice. NETs may provide new targets for DVT drug development.
AB - BACKGROUND: Upon activation, neutrophils can release nuclear material known as neutrophil extracellular traps (NETs), which were initially described as a part of antimicrobial defense. Extracellular chromatin was recently reported to be prothrombotic in vitro and to accumulate in plasma and thrombi of baboons with experimental deep vein thrombosis (DVT).OBJECTIVE: To explore the source and role of extracellular chromatin in DVT.METHODS: We used an established murine model of DVT induced by flow restriction (stenosis) in the inferior vena cava (IVC).RESULTS: We demonstrate that the levels of extracellular DNA increase in plasma after 6 h IVC stenosis, compared with sham-operated mice. Immunohistochemical staining revealed the presence of Gr-1-positive neutrophils in both red (RBC-rich) and white (platelet-rich) parts of thrombi. Citrullinated histone H3 (CitH3), an element of NETs' structure, was present only in the red part of thrombi and was frequently associated with the Gr-1 antigen. Immunofluorescent staining of thrombi showed proximity of extracellular CitH3 and von Willebrand factor (VWF), a platelet adhesion molecule crucial for thrombus development in this model. Infusion of Deoxyribonuclease 1 (DNase 1) protected mice from DVT after 6 h and also 48 h IVC stenosis. Infusion of an unfractionated mixture of calf thymus histones increased plasma VWF and promoted DVT early after stenosis application.CONCLUSIONS: Extracellular chromatin, likely originating from neutrophils, is a structural part of a venous thrombus and both the DNA scaffold and histones appear to contribute to the pathogenesis of DVT in mice. NETs may provide new targets for DVT drug development.
KW - Animals
KW - Chromatin
KW - DNA
KW - Histones
KW - Mice
KW - Neutrophils
KW - Vena Cava, Inferior
KW - Venous Thrombosis
KW - von Willebrand Factor
U2 - 10.1111/j.1538-7836.2011.04544.x
DO - 10.1111/j.1538-7836.2011.04544.x
M3 - SCORING: Journal article
C2 - 22044575
VL - 10
SP - 136
EP - 144
JO - J THROMB HAEMOST
JF - J THROMB HAEMOST
SN - 1538-7933
IS - 1
ER -