Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage
Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage
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重组 ADAMTS 13 减轻脑出血后的脑损伤
DOI：
10.1161/strokeaha.115.009526
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发表时间：
2015-09-01
期刊：
影响因子：
8.3
通讯作者：
Fan, Wenying
中科院分区：
文献类型：
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作者：
Cai, Ping;Luo, Haiyu;Fan, Wenying
背景和目的-炎症反应和血脑屏障（BBB）功能障碍在脑出血（ICH）后脑损伤中起重要作用。金属蛋白酶ADAMTS 13（具有血小板反应蛋白I型基序的解整合素和金属蛋白酶，成员13）显示通过其对血管性血友病因子的蛋白水解作用来限制炎症反应。在本研究中，我们解决的作用ADAMTS 13后，实验ICH. Methods脑出血诱导小鼠脑内输注自体血。在24小时时定量血肿周围炎症反应、基质金属蛋白酶-9和细胞间粘附分子-1水平、脑毛细血管周细胞覆盖率和BBB通透性。功能结果，脑水肿和出血性病变体积在第3天进行定量。结果重组ADAMTS 13（rADAMTS 13）治疗降低了ICH后趋化因子和细胞因子的水平，髓过氧化物酶活性，小胶质细胞活化和中性粒细胞募集。rADAMTS 13还降低了脂多糖刺激的脑内皮细胞中白细胞介素-6的表达，而重组血管性血友病因子逆转了这种作用。rADAMTS 13的抗炎作用伴随着细胞间粘附分子-1的表达减少和基质金属蛋白酶的活化减少，增强脑微血管周细胞覆盖，并减弱BBB破坏。此外，中性粒细胞耗竭保护免受BBB损伤，并且rADAMTS 13治疗没有进一步的有益效果。最后，治疗小鼠与rADAMTS 13减少脑水肿和出血性病变体积和改善神经functions. Conclusions-我们的研究结果揭示了rADAMTS 13在调节病理炎症和血脑屏障功能的重要性，并建议rADAMTS 13可能为ICH提供一种新的治疗策略。
Background and Purpose-Inflammatory responses and blood-brain barrier (BBB) dysfunction play important roles in brain injury after intracerebral hemorrhage (ICH). The metalloprotease ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type I motif, member 13) was shown to limit inflammatory responses through its proteolytic effects on von Willebrand factor. In the present study, we addressed the role of ADAMTS 13 after experimental ICH.Methods-ICH was induced in mice by intracerebral infusion of autologous blood. The peri-hematomal inflammatory responses, levels of matrix metalloproteinase-9 and intercellular adhesion molecule-1, pericyte coverage on brain capillaries, and BBB permeability were quantified at 24 hours. Functional outcomes, cerebral edema, and hemorrhagic lesion volume were quantified at day 3.Results-Treatment with recombinant ADAMTS 13 (rADAMTS 13) reduced the levels of chemokines and cytokines, myeloperoxidase activity, and microglia activation and neutrophil recruitment after ICH. rADAMTS 13 also decreased interleukin-6 expression in brain endothelial cells stimulated by lipopolysaccharide, whereas recombinant von Willebrand factor reversed this effect. The anti-inflammatory effect of rADAMTS 13 was accompanied by reduced expression of intercellular adhesion molecule-1 and less activation of matrix metalloproteinase, enhanced pericyte coverage of brain microvessels, and attenuated BBB disruption. Furthermore, neutrophil depletion protected against BBB damage, and rADAMTS 13 treatment had no further beneficial effect. Finally, treatment of mice with rADAMTS 13 reduced cerebral edema and hemorrhagic lesion volume and improved neurological functions.Conclusions-Our findings reveal the importance of rADAMTS 13 in regulating pathological inflammation and BBB function and suggest that rADAMTS 13 may provide a new therapeutic strategy for ICH.