Deficiency in serine protease inhibitor neuroserpin exacerbates ischemic brain injury by increased postischemic inflammation.
Deficiency in serine protease inhibitor neuroserpin exacerbates ischemic brain injury by increased postischemic inflammation.
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DOI：
10.1371/journal.pone.0063118
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Magnus T
中科院分区：
文献类型：
--
作者：
Gelderblom M;Neumann M;Ludewig P;Bernreuther C;Krasemann S;Arunachalam P;Gerloff C;Glatzel M;Magnus T
唯一获批的缺血性卒中药物治疗是静脉内给予纤溶酶原激活剂（tPA），以使闭塞的脑血管再通。不仅再灌注，而且tPA本身也可以诱导炎症反应。小胶质细胞是中枢神经系统的先天免疫细胞，也是中风时最先被激活的免疫细胞。Neuroserpin是tPA的内源性抑制剂，在脑缺血后上调。为了研究神经丝氨酸蛋白酶抑制剂依赖的脑卒中神经保护机制，我们研究了神经丝氨酸蛋白酶抑制剂缺陷（Ns-/-）小鼠的颞叶局灶性缺血性脑卒中动物模型。在neuroserpin缺陷小鼠中，即使缺血脑中的纤溶活性增加，脑体积和神经学结果也更差。NS−/−小鼠中促炎性小胶质细胞活化的选择性增加抵消了梗死面积的增加。我们的研究结果表明，过度的小胶质细胞激活在Ns-/-小鼠介导的tPA的活性增加。这种激活导致更差的结果，进一步强调了tPA的潜在有害促炎作用。
The only approved pharmacological treatment for ischemic stroke is intravenous administration of plasminogen activator (tPA) to re-canalize the occluded cerebral vessel. Not only reperfusion but also tPA itself can induce an inflammatory response. Microglia are the innate immune cells of the central nervous system and the first immune cells to become activated in stroke. Neuroserpin, an endogenous inhibitor of tPA, is up-regulated following cerebral ischemia. To examine neuroserpin-dependent mechanisms of neuroprotection in stroke, we studied neuroserpin deficient (Ns−/−) mice in an animal model of temporal focal ischemic stroke. Infarct size and neurological outcome were worse in neuroserpin deficient mice even though the fibrinolytic activity in the ischemic brain was increased. The increased infarct size was paralleled by a selective increase in proinflammatory microglia activation in Ns−/− mice. Our results show excessive microglial activation in Ns−/− mice mediated by an increased activity of tPA. This activation results in a worse outcome further underscoring the potential detrimental proinflammatory effects of tPA.
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