BLOOD：PKM2促进中性粒细胞激活和脑血栓炎症对缺血性中风的治疗意义

2021-09-22 MedSci原创 MedSci原创

目前，急性缺血性中风可通过使用重组组织纤溶酶原激活剂(rtPA)静脉溶栓和/或机械血栓切除来治疗。虽然这两种方法都是有效的，但它们也有局限性。例如，在rtPA中，近17-34%的卒中患者给药后观察到早

目前，急性缺血性中风可通过使用重组组织纤溶酶原激活剂(rtPA)静脉溶栓和/或机械血栓切除来治疗。虽然这两种方法都是有效的，但它们也有局限性。例如，在rtPA中，近17-34%的卒中患者给药后观察到早期动脉再闭塞和不甚理想的预后结局。这些局限性提示了我们对新的辅助治疗的需求，以有效提高卒中再灌注治疗效果。

近日有研究团队发现，在人类和小鼠中，缺血性中风发作后，中性粒细胞中的核丙酮酸激酶肌肉2 (PKM2) 是全身性炎症的调节剂，他们利用已有合并症的小鼠模型确定了PKM2在中风发病机理中的作用。

在野生型 (PKM2fl/flLysMCre) 和高脂血症背景 (PKM2fl/flLysMCre Apoe-/-) 上生成了新型骨髓细胞特异性 PKM2 ^-/-小鼠。对照是同窝 PKM2 ^fl/fl LysMCre^-或 PKM2 ^fl/fl LysMCre ^- Apoe ^-/-小鼠。

骨髓细胞中PKM2的遗传缺失限制了脑缺血/再灌注后外周中性粒细胞的炎症反应，并减少了中性粒细胞的细胞外陷阱，这表明PKM2在中风时会促进中性粒细胞的过度活化。

在丝状体和自体凝块/rtPA 中风模型中，无论性别如何，野生型或高脂血症小鼠髓样细胞中PKM2的缺失都会减少梗塞并增强长期感觉运动恢复。激光散斑成像显示髓样细胞特异性PKM2缺陷小鼠的局部脑血流量改善，同时伴有缺血后脑血栓炎症（脑内纤维蛋白(原）、血小板(cd41阳性)沉积、中性粒细胞浸润和炎症细胞因子)的减少。

机制上，PKM2通过促进STAT3磷酸化来调节外周中性粒细胞的缺血后炎症。为了增强翻译意义，研究团队使用小分子抑制PKM2核易位，发现中性粒细胞过度活化显著减少，并改善了卒中后的短期和长期功能预后。

总的来说，这些发现表明PKM2是一种新的治疗靶点，可以改善再灌注后的脑挽救和恢复。

原始出处：

Nirav Dhanesha, Rakesh B. Patel, Prakash Doddapattar, Madankumar Ghatge, Gagan D Flora, Manish Jain, Daniel Thedens, Heena Olalde, Mariia Kumskova, Enrique Leira, Anil K Chauhan; PKM2 promotes neutrophil activation and cerebral thrombo-inflammation: Therapeutic implications for ischemic stroke. Blood 2021; blood.2021012322. doi: https://doi.org/10.1182/blood.2021012322

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2022-02-04 guihongzh

#缺血性#

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2022-05-08 liuquanmn

#脑血栓#

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2022-06-24 hanhaisha2008

#治疗意义#

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2021-09-24 yykkxiaodou

#中性粒细胞#

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2021-09-24 by2009

#PKM2#

44 0
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2021-09-24 hywen7329

#缺血性中风#

47 0

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BLOOD：PKM2促进中性粒细胞激活和脑血栓炎症对缺血性中风的治疗意义

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