Neutrophils Obstructing Brain Capillaries Are a Major Cause of No-Reflow in Ischemic Stroke
Neutrophils Obstructing Brain Capillaries Are a Major Cause of No-Reflow in Ischemic Stroke
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DOI：
10.1016/j.celrep.2020.108260
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发表时间：
2020-10-13
期刊：
影响因子：
8.8
通讯作者：
Wegener, Susanne
中科院分区：
文献类型：
--
作者：
El Amki, Mohamad;Glueck, Chaim;Wegener, Susanne
尽管在大血管闭塞性中风中成功取出血栓，但仍有大约 50% 的患者出现不良的临床结果。这种功能性再灌注失败的机制仍然未知，并且缺乏治疗选择。在小鼠大脑中动脉（MCA）中风的凝血酶模型中，我们发现，尽管近端 MCA 成功溶栓再通，但皮质血流并未完全恢复。使用体内双光子成像，我们证明这是由于粘附于远端毛细血管段的中性粒细胞阻塞了梗死核心和半暗带中类似20%-30%的毛细血管的微血管。使用抗 Ly6G 抗体消耗循环中性粒细胞可以恢复微血管灌注，而不会增加出血并发症的发生率。引人注目的是，用抗 Ly6G 治疗的小鼠的梗塞面积和功能缺陷更小。因此，我们提出脑毛细血管的中性粒细胞停滞导致再灌注失败，这为缺血性中风提供了有希望的治疗途径。
Despite successful clot retrieval in large vessel occlusion stroke, similar to 50% of patients have an unfavorable clinical outcome. The mechanisms underlying this functional reperfusion failure remain unknown, and therapeutic options are lacking. In the thrombin-model of middle cerebral artery (MCA) stroke in mice, we show that, despite successful thrombolytic recanalization of the proximal MCA, cortical blood flow does not fully recover. Using in vivo two-photon imaging, we demonstrate that this is due to microvascular obstruction of similar to 20%-30% of capillaries in the infarct core and penumbra by neutrophils adhering to distal capillary segments. Depletion of circulating neutrophils using an anti-Ly6G antibody restores microvascular perfusion without increasing the rate of hemorrhagic complications. Strikingly, infarct size and functional deficits are smaller in mice treated with anti-Ly6G. Thus, we propose neutrophil stalling of brain capillaries to contribute to reperfusion failure, which offers promising therapeutic avenues for ischemic stroke.