高血糖加剧血栓炎症促使脑梗死扩大和出血性转化。

Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation.

作者信息

Desilles Jean-Philippe, Syvannarath Varouna, Ollivier Véronique, Journé Clément, Delbosc Sandrine, Ducroux Célina, Boisseau William, Louedec Liliane, Di Meglio Lucas, Loyau Stéphane, Jandrot-Perrus Martine, Potier Louis, Michel Jean-Baptiste, Mazighi Mikael, Ho-Tin-Noé Benoit

机构信息

From the Laboratory of Vascular Translational Science, U1148 Institut National de la Santé et de la Recherche Médicale (INSERM), Univ Paris Diderot, Sorbonne Paris Cite, France (J.-P.D., V.S., V.O., C.J., S.D., C.D., W.B., L.L., L.D.M., S.L., M.J.-P., J.-B.M., M.M., B.H.-T.-N.); Department of Interventional Neuroradiology, Rothschild Foundation Hospital, Paris, France (J.-P.D., W.B., M.M.); DHU NeuroVasc, Paris, France (J.-P.D., M.M.); FRIM-Paris 7 University, Paris, France (C.J.); and Department of Diabetology AP-HP, Bichat Hospital, Paris, France (L.P.).

出版信息

Stroke. 2017 Jul;48(7):1932-1940. doi: 10.1161/STROKEAHA.117.017080. Epub 2017 May 19.

DOI:10.1161/STROKEAHA.117.017080

PMID:28526762

Abstract

BACKGROUND AND PURPOSE

Admission hyperglycemia is associated with a poor outcome in acute ischemic stroke. How hyperglycemia impacts the pathophysiology of acute ischemic stroke remains largely unknown. We investigated how preexisting hyperglycemia increases ischemia/reperfusion cerebral injury.

METHODS

Normoglycemic and streptozotocin-treated hyperglycemic rats were subjected to transient middle cerebral artery occlusion. Infarct growth and brain perfusion were assessed by magnetic resonance imaging. Markers of platelet, coagulation, and neutrophil activation were measured in brain homogenates and plasma. Downstream microvascular thromboinflammation (DMT) was investigated by intravital microscopy.

RESULTS

Hyperglycemic rats had an increased infarct volume with an increased blood-brain barrier disruption and hemorrhagic transformation rate compared with normoglycemic rats. Magnetic resonance imaging scans revealed that hyperglycemia enhanced and accelerated lesion growth and was associated with hemorrhagic transformation originating from territories that were still not completely reperfused at 1 hour after middle cerebral artery recanalization. Intravital microscopy and analysis of brain homogenates showed that DMT began immediately after middle cerebral artery occlusion and was exacerbated by hyperglycemia. Measurement of plasma serotonin and matrix metalloproteinase-9 indicated that platelets and neutrophils were preactivated in hyperglycemic rats. Neutrophils from hyperglycemic diabetic patients showed increased adhesion to endothelial cells as compared with neutrophils from normoglycemic donors in flow chamber experiments.

CONCLUSIONS

We show that hyperglycemia primes the thromboinflammatory cascade, thus, amplifying middle cerebral artery occlusion-induced DMT. DMT exacerbation in hyperglycemic rats impaired reperfusion and precipitated neurovascular damage, blood-brain barrier disruption, and hemorrhagic transformation. Our results designate DMT as a possible target for reduction of the deleterious impact of hyperglycemia in acute ischemic stroke.

摘要

背景与目的

入院时高血糖与急性缺血性卒中的不良预后相关。高血糖如何影响急性缺血性卒中的病理生理学仍 largely 未知。我们研究了预先存在的高血糖如何增加缺血/再灌注脑损伤。

方法

将血糖正常和经链脲佐菌素治疗的高血糖大鼠进行短暂性大脑中动脉闭塞。通过磁共振成像评估梗死灶生长和脑灌注。在脑匀浆和血浆中测量血小板、凝血和中性粒细胞活化的标志物。通过活体显微镜检查研究下游微血管血栓性炎症（DMT）。

结果

与血糖正常的大鼠相比，高血糖大鼠的梗死体积增加，血脑屏障破坏和出血转化率增加。磁共振成像扫描显示，高血糖增强并加速了病变生长，并且与大脑中动脉再通后 1 小时仍未完全再灌注区域的出血转化有关。活体显微镜检查和脑匀浆分析表明，DMT 在大脑中动脉闭塞后立即开始，并因高血糖而加剧。血浆 5-羟色胺和基质金属蛋白酶-9 的测量表明，高血糖大鼠中的血小板和中性粒细胞被预激活。在流动腔实验中，与血糖正常供体的中性粒细胞相比，高血糖糖尿病患者的中性粒细胞对内皮细胞的粘附增加。