Systemic inflammatory stimulus potentiates the acute phase and CXC chemokine responses to experimental stroke and exacerbates brain damage via interleukin-1- and neutrophil-dependent mechanisms
Systemic inflammatory stimulus potentiates the acute phase and CXC chemokine responses to experimental stroke and exacerbates brain damage via interleukin-1- and neutrophil-dependent mechanisms
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DOI：
10.1523/jneurosci.5376-06.2007
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发表时间：
2007-04-18
影响因子：
5.3
通讯作者：
Allan, Stuart M.
中科院分区：
文献类型：
--
作者：
McColl, Barry W.;Rothwell, Nancy J.;Allan, Stuart M.
全身性炎症刺激，如感染，会增加中风的风险，并与较差的临床结果相关。全身性炎症刺激对中风影响的潜在机制尚未明确界定。我们研究了全身性炎症对实验性中风的影响以及所涉及的潜在机制。大脑中动脉（MCAo）腔内丝线阻塞诱导局灶性脑缺血。全身性脂多糖（LPS）给药会加剧MCAo后24小时的脑损伤和神经功能缺损。这种加剧严重依赖于白细胞介素（IL）-1，因为联合给予IL - 1受体拮抗剂可消除LPS对脑损伤的影响。全身性给予IL - 1增加缺血性损伤的程度与LPS相似，并且也会加剧脑水肿。IL - 1显著增强急性期蛋白、血清淀粉样蛋白A和IL - 6以及中性粒细胞选择性CXC趋化因子KC和巨噬细胞炎症蛋白 - 2的循环水平。在缺血性损伤发生变化之前，IL - 1会加重中性粒细胞的动员和皮质中性粒细胞浸润。中性粒细胞减少可消除全身性IL - 1的损伤作用。这些数据首次表明，急性全身性炎症刺激对实验性中风后的结果有害，并强调IL - 1是这种模式中的关键介质。我们的数据表明，IL - 1通过诱导CXC趋化因子增强中性粒细胞动员是这种效应的一种潜在机制。我们的结果可能有助于解释伴有感染的中风患者较差的预后，并且可能对涉及神经血管改变的神经退行性疾病有影响，例如阿尔茨海默病，在这种疾病中全身性炎症可调节疾病进展。
Systemic inflammatory stimuli, such as infection, increase the risk of stroke and are associated with poorer clinical outcome. The mechanisms underlying the impact of systemic inflammatory stimuli on stroke are not well defined. We investigated the impact of systemic inflammation on experimental stroke and potential mechanisms involved. Focal cerebral ischemia was induced by intraluminal filament occlusion of the middle cerebral artery (MCAo). Brain damage and neurological deficit 24 h after MCAo were exacerbated by systemic lipopolysaccharide (LPS) administration. This exacerbation was critically dependent on interleukin (IL)-1, because coadministration of IL-1 receptor antagonist abolished the effect of LPS on brain damage. Systemic administration of IL-1 increased ischemic damage to a similar extent as LPS and also exacerbated brain edema. IL-1 markedly potentiated circulating levels of the acute phase proteins, serum amyloid A and IL-6, and the neutrophil-selective CXC chemokines, KC and macrophage inflammatory protein-2. Neutrophil mobilization and cortical neutrophil infiltration were aggravated by IL-1 before changes in ischemic damage. Neutropenia abolished the damaging effects of systemic IL-1. These data show for the first time that an acute systemic inflammatory stimulus is detrimental to outcome after experimental stroke and highlight IL-1 as a critical mediator in this paradigm. Our data suggest IL-1-induced potentiation of neutrophil mobilization via CXC chemokine induction is a putative mechanism underlying this effect. Our results may help to explain the poorer outcome in stroke patients presenting with infection and may have implications for neurodegenerative diseases involving neurovascular alterations, such as Alzheimer's disease, in which systemic inflammation can modulate disease progression.