Protective and detrimental effects of neuroectodermal cell-derived tissue factor in mouse models of stroke.
Protective and detrimental effects of neuroectodermal cell-derived tissue factor in mouse models of stroke.
复制标题
神经外胚层细胞源性组织因子对中风小鼠模型的保护作用和有害作用。
DOI：
10.1172/jci.insight.86663
复制
发表时间：
2016
期刊：
影响因子：
8
通讯作者：
Pawlinski,Rafal
中科院分区：
文献类型：
--
作者：
Wang,Shaobin;Reeves,Brandi;Sparkenbaugh,EricaM;Russell,Janice;Soltys,Zbigniew;Zhang,Hua;Faber,JamesE;Key,NigelS;Kirchhofer,Daniel;Granger,DNeil;Mackman,Nigel;Pawlinski,Rafal
在CNS内，止血反应失调导致出血性和缺血性卒中。组织因子（TF）是外源性凝血级联反应的主要起始因子，在止血中起重要作用，也有助于血栓形成。使用遗传学和药理学的方法，我们的特点是神经外胚层（NE）细胞TF中风的病理生理学的贡献。我们使用了不同TF表达水平的小鼠，发现星形胶质细胞TF活性降低至WT水平的约5%仍足以维持出血性卒中后的止血，但也足够低以减轻炎症，减少对血脑屏障的损伤，并改善缺血性卒中后的结局。在缺血性中风的再灌注阶段，TF的药理学抑制可减轻神经元损伤，改善行为缺陷，并防止小鼠死亡。我们的数据表明，NE细胞TF限制与缺血性卒中向出血性卒中转变相关的出血并发症，也有助于缺血性卒中后的再灌注损伤。CNS中TF的高水平表达可能是创伤性脑损伤后限制脑出血（ICH）的选择性压力的结果，但在现代，缺血性卒中后增加缺血再灌注损伤的额外风险。
Within the CNS, a dysregulated hemostatic response contributes to both hemorrhagic and ischemic strokes. Tissue factor (TF), the primary initiator of the extrinsic coagulation cascade, plays an essential role in hemostasis and also contributes to thrombosis. Using both genetic and pharmacologic approaches, we characterized the contribution of neuroectodermal (NE) cell TF to the pathophysiology of stroke. We used mice with various levels of TF expression and found that astrocyte TF activity reduced to ~5% of WT levels was still sufficient to maintain hemostasis after hemorrhagic stroke but was also low enough to attenuate inflammation, reduce damage to the blood-brain barrier, and improve outcomes following ischemic stroke. Pharmacologic inhibition of TF during the reperfusion phase of ischemic stroke attenuated neuronal damage, improved behavioral deficit, and prevented mortality of mice. Our data demonstrate that NE cell TF limits bleeding complications associated with the transition from ischemic to hemorrhagic stroke and also contributes to the reperfusion injury after ischemic stroke. The high level of TF expression in the CNS is likely the result of selective pressure to limit intracerebral hemorrhage (ICH) after traumatic brain injury but, in the modern era, poses the additional risk of increased ischemia-reperfusion injury after ischemic stroke.