Inhibition of caspase-1-mediated inflammasome activation reduced blood coagulation in cerebrospinal fluid after subarachnoid haemorrhage.
Inhibition of caspase-1-mediated inflammasome activation reduced blood coagulation in cerebrospinal fluid after subarachnoid haemorrhage.
复制标题
抑制 caspase-1 介导的炎症小体激活可降低蛛网膜下腔出血后脑脊液中的凝血
DOI：
10.1016/j.ebiom.2022.103843
复制
发表时间：
2022-03
期刊：
影响因子：
11.1
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Fang Y;Wang X;Lu J;Shi H;Huang L;Shao A;Zhang A;Liu Y;Ren R;Lenahan C;Tang J;Zhang J;Zhang JH;Chen S
脑脊液(CSF)中的神经炎症和凝血反应是蛛网膜下腔出血(SAH)预后不良的原因之一。我们探讨了caspase-1介导的炎性小体激活在SAH后脑脊液外源性凝血中的作用。分析SAH后人脑脊液中caspase-1的蛋白质组学变化及其与外源性凝血因子的相关性。采用大鼠SAH模型，研究SAH后脑炎性小体和外源性凝血蛋白的时间进程和细胞定位。通过VX-765对caspase-1的药理抑制作用，探讨caspase-1在SAH大鼠血液清除和脑脊液循环中的作用。原代培养的星形胶质细胞用来评价caspase-1在血红蛋白诱导的下垂和组织因子(TF)产生/释放中的作用。蛛网膜下腔出血后人脑脊液中的神经炎症和凝血功能被激活。Caspase-1水平与外源性凝血因子水平显著相关。SAH后星形胶质细胞上活化的caspase-1和外源性凝血启动物Tf增加。VX-765短期内通过抑制炎症性神经炎和TF诱导的纤维蛋白沉积而促进脑脊液循环和血液清除，从而减轻神经功能障碍；长期内通过预防SAH后海马神经元丢失和脑积水改善学习记忆能力。VX-765可减少血红蛋白诱导的原代星形胶质细胞炎症性下垂和TF的产生/释放。VX-765对caspase-1的抑制可能是一种潜在的治疗SAH后脑脊液中神经炎症和凝血的方法。本研究得到了美国国立卫生研究院和中国国家自然科学基金的资助。
Neuroinflammation and blood coagulation responses in cerebrospinal fluid (CSF) contribute to the poor outcome associated with subarachnoid haemorrhage (SAH). We explored the role of caspase-1-mediated inflammasome activation on extrinsic blood coagulation in CSF after SAH. Post-SAH proteomic changes and correlation between caspase-1 with extrinsic coagulation factors in human CSF after SAH were analysed. Time course and cell localisation of brain inflammasome and extrinsic coagulation proteins after SAH were explored in a rat SAH model. Pharmacological inhibition of caspase-1 via VX-765 was used to explore the role of caspase-1 in blood clearance and CSF circulation after SAH in rats. Primary astrocytes were used to evaluate the role of caspase-1 in haemoglobin-induced pyroptosis and tissue factor (TF) production/release. Neuroinflammation and blood coagulation activated after SAH in human CSF. The caspase-1 levels significantly correlated with the extrinsic coagulation factors. The activated caspase-1 and extrinsic coagulation initiator TF was increased on astrocytes after SAH in rats. VX-765 attenuated neurological deficits by accelerating CSF circulation and blood clearance through inhibiting pyroptotic neuroinflammation and TF-induced fibrin deposition in the short-term, and improved learning and memory capacity by preventing hippocampal neuronal loss and hydrocephalus in the long-term after SAH in rats. VX-765 reduced haemoglobin-induced pyroptosis and TF production/release in primary astrocytes. Inhibition of caspase-1 by VX-765 appears to be a potential treatment against neuroinflammation and blood coagulation in CSF after SAH. This study was supported by National Institutes of Health of United States of America, and National Natural Science Foundation of China.
登录
查看更多内容
影响因子：
16.6
作者：
Flores J;Noël A;Foveau B;Lynham J;Lecrux C;LeBlanc AC
通讯作者：
LeBlanc AC
Caspase-1 抑制通过极化 M2 小胶质细胞/巨噬细胞和抑制 NF-κ B 激活介导实验性卒中的神经保护
DOI：
10.1016/j.bbrc.2019.03.202
发表时间：
2019-05-28
影响因子：
3.1
作者：
Li, Qian;Dai, Zhenguo;Wang, Lihua
通讯作者：
Wang, Lihua
影响因子：
4.1
作者：
Galea, James;Ogungbenro, Kayode;Tyrrell, Pippa
通讯作者：
Tyrrell, Pippa
影响因子：
15.9
作者：
EDDLESTON, M;DELATORRE, JC;MACKMAN, N
通讯作者：
MACKMAN, N
影响因子：
4.1
作者：
Aldrich, E. Francois;Higashida, Randall;Bruder, Nicolas
通讯作者：
Bruder, Nicolas