ADAMTS13 reduces VWF-mediated acute inflammation following focal cerebral ischemia in mice.
ADAMTS13 reduces VWF-mediated acute inflammation following focal cerebral ischemia in mice.
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DOI：
10.1111/j.1538-7836.2012.04822.x
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
Chauhan AK
中科院分区：
文献类型：
--
作者：
Khan MM;Motto DG;Lentz SR;Chauhan AK
ADAMTS13 将高度活跃的超大血管性血友病因子 (ULVWF) 多聚体裂解成更小且活性较低的形式。目前尚不清楚 VWF 介导的炎症过程是否可能在 ADAMTS13 缺陷导致的脑损伤加剧中发挥作用。我们测试了以下假设：ADAMTS13 缺陷对缺血性脑损伤的有害影响是通过 VWF 依赖性增强血管炎症介导的。右侧大脑中动脉闭塞 60 分钟，诱发短暂性局灶性脑缺血。再灌注损伤后23小时评估梗塞区域的髓过氧化物酶（MPO）活性和炎症细胞因子。通过免疫组织化学对梗塞及其周围区域内的中性粒细胞浸润进行定量。我们报告 ADAMTS13 缺陷小鼠表现出明显扩大的梗塞面积，与髓过氧化物酶 (MPO) 活性增加、中性粒细胞浸润以及促炎细胞因子白细胞介素 6 (IL-6) 和肿瘤坏死因子 - α (TNF-α) 表达一致。相比之下，VWF缺陷小鼠的MPO活性、中性粒细胞浸润和炎症细胞因子诱导显着降低，证明了VWF在这些炎症过程中的作用。 ADAMTS13 和 VWF 缺陷小鼠表现出相同炎症参数的相同减少，表明在 ADAMTS13 缺陷小鼠中观察到的炎症增加是 VWF 依赖性的。最后，在 ADAMTS13 缺陷小鼠中观察到的梗塞面积增加被先前的中性粒细胞免疫耗竭完全消除，这表明急性炎症在 ADAMTS13 缺陷情况下发生的脑损伤加剧中具有因果作用。这些发现为 ADAMTS13 减少缺血性中风后 VWF 介导的急性脑炎症提供了新的证据。
ADAMTS13 cleaves hyperactive ultra-large von Willebrand factor (ULVWF) multimers into smaller and less active forms. It remains unknown whether VWF-mediated inflammatory processes may play a role in the enhanced brain injury due to ADAMTS13 deficiency. We tested the hypothesis that the deleterious effect of ADAMTS13 deficiency on ischemic brain injury is mediated through VWF-dependent enhanced vascular inflammation. Transient focal cerebral ischemia was induced by 60 minutes of occlusion of the right middle cerebral artery. Myeloperoxidase (MPO) activity and inflammatory cytokines in the infarcted region was evaluated 23 hours after reperfusion injury. Neutrophil infiltration within the infarct and surrounding areas was quantitated by immunohistochemistry. We report that ADAMTS13-deficient mice exhibited significantly enlarged infarct size, concordant with increased myeloperoxidase (MPO) activity, neutrophil infiltration, and expression of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor- α (TNF-α). In contrast, VWF-deficient mice exhibited significantly reduced MPO activity, neutrophil infiltration, and inflammatory cytokine induction, demonstrating a role for VWF in these inflammatory processes. Mice deficient for both ADAMTS13 and VWF exhibited an identical reduction of the same inflammatory parameters, demonstrating that the increased inflammation observed in ADAMTS13-deficient mice is VWF-dependent. Finally, the increased infarct size observed in ADAMTS13-deficient mice was completely abrogated by prior immunodepletion of neutrophils, demonstrating a causal role for acute inflammation in the enhanced brain injury that occurs in the setting of ADAMTS13 deficiency. These findings provide new evidence for ADAMTS13 in reducing VWF-mediated acute cerebral inflammation following ischemic stroke.
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影响因子：
20.3
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
20.3
作者：
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通讯作者：
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DOI：
10.1073/pnas.0803945105
发表时间：
2008-11-25
影响因子：
11.1
作者：
Breckwoldt, Michael O.;Chen, John W.;Weissleder, Ralph
通讯作者：
Weissleder, Ralph