Pharmacological Modulation of Neutrophil Extracellular Traps Reverses Thrombotic Stroke tPA (Tissue-Type Plasminogen Activator) Resistance
Pharmacological Modulation of Neutrophil Extracellular Traps Reverses Thrombotic Stroke tPA (Tissue-Type Plasminogen Activator) Resistance
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DOI：
10.1161/strokeaha.119.026848
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发表时间：
2019-11-01
期刊：
影响因子：
8.3
通讯作者：
Moro, Maria A.
中科院分区：
文献类型：
--
作者：
Pena-Martinez, Carolina;Duran-Laforet, Violeta;Moro, Maria A.
背景和目的--闭塞动脉再通是卒中治疗的主要目标。遗憾的是，血管内治疗并不总是有效的，组织型纤溶酶原激活剂(TPA)治疗受到治疗窗口狭窄的限制；重要的是，tPA应用后早期动脉再通率低，尤其是对富含血小板的血栓。这种tPA耐药性的机制还不是很清楚。由于中性粒细胞胞外陷阱(Net)与这种情况有关，我们的目的是研究净药物调节是否可以逆转tPA抵抗，以及以前与Net形成相关的TLR4(Toll样受体4)在血栓形成中的作用。方法：为了达到这个目标，我们使用了一种小鼠光血栓卒中模型，它产生了一种无纤维蛋白的血栓，主要由聚集的血小板和从人类中风患者获得的血栓组成。结果：我们的结果表明：(1)给予DNase-I，它促进Nets的溶解，而不是tPA，使闭塞的血管重新通畅，改善光栓性卒中的预后；(2)预防性治疗，阻止Net的形成，完全阻止血栓性闭塞；(3)血小板TLR4介导光血栓性卒中后的Net的形成；(4)DNase-I有效地溶解来自缺血性卒中患者的新鲜富含血小板的血栓。结论--因此，我们的数据为卒中后富含血小板的血栓再通开辟了新的途径，尤其是克服tPA抵抗。
Background and Purpose- Recanalization of the occluded artery is a primary goal in stroke treatment. Unfortunately, endovascular treatment is not always available, and tPA (tissue-type plasminogen activator) therapy is limited by its narrow therapeutic window; importantly, the rate of early arterial recanalization after tPA administration is low, especially for platelet-rich thrombi. The mechanisms for this tPA resistance are not well known. Since neutrophil extracellular traps (NETs) have been implicated in this setting, our aim was to study whether NET pharmacological modulation can reverse tPA resistance and the role of TLR4 (Toll-like receptor 4), previously related to NET formation, in thrombosis. Methods- To this goal, we have used a mouse photothrombotic stroke model, which produces a fibrin-free thrombus composed primarily of aggregated platelets and thrombi obtained from human stroke patients. Results- Our results demonstrate that (1) administration of DNase-I, which promotes NETs lysis, but not of tPA, recanalizes the occluded vessel improving photothrombotic stroke outcome; (2) a preventive treatment with Cl-amidine, impeding NET formation, completely precludes thrombotic occlusion; (3) platelet TLR4 mediates NET formation after photothrombotic stroke; and (4) ex vivo fresh platelet-rich thrombi from ischemic stroke patients are effectively lysed by DNase-I. Conclusions- Hence, our data open new avenues for recanalization of platelet-rich thrombi after stroke, especially to overcome tPA resistance.