Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice
Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice
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DOI：
10.1523/jneurosci.2674-08.2008
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发表时间：
2008-09-17
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.
全身性炎症事件，如感染，增加中风的风险，并与更差的结果，但这种临床重要影响的介质是未知的。我们的目的是阐明全身炎症对小鼠轻度缺血性脑损伤的有害作用的机制。通过外周白细胞介素-1 β（IL-1 β）激发和短暂大脑中动脉闭塞（MCAo）局灶性脑缺血诱导小鼠全身炎症。全身性炎症通过将短暂的紧密连接蛋白claudin-5破坏转化为持续的破坏而引起血脑屏障（BBB）破坏动力学的改变，并且还显著加剧了对脑血管基底层蛋白胶原IV的破坏。这些改变与全身炎症诱导的神经血管明胶溶解活性增加有关，这是由MCAo后IL-1 β激发小鼠脑中嗜中性粒细胞衍生的基质金属蛋白酶-9（MMP-9）增加5倍介导的。MMP-9的特异性抑制消除了全身炎症对持续性而非急性的claudin-5破坏的影响，claudin-5与脑血管肌球蛋白轻链的磷酸化有关。MMP-9抑制还减弱了全身性炎症对脑损伤、水肿、神经功能缺损和出血性转化发生率的有害影响。这些数据表明，由增强的嗜中性粒细胞衍生的神经血管MMP-9活性引起的从短暂到持续的BBB破坏的转变是全身炎症引起的缺血性脑损伤恶化的关键机制。这些机制可能会导致中风患者的不良临床结果与前期感染。
Systemic inflammatory events, such as infection, increase the risk of stroke and are associated with worse outcome, but the mediators of this clinically important effect are unknown. Our aim here was to elucidate mechanisms contributing to the detrimental effects of systemic inflammation on mild ischemic brain injury in mice. Systemic inflammation was induced in mice by peripheral interleukin-1 beta (IL-1 beta) challenge and focal cerebral ischemia by transient middle cerebral artery occlusion (MCAo). Systemic inflammation caused an alteration in the kinetics of blood-brain barrier (BBB) disruption through conversion of a transient to a sustained disruption of the tight junction protein, claudin-5, and also markedly exacerbated disruption to the cerebrovascular basal lamina protein, collagen-IV. These alterations were associated with a systemic inflammation-induced increase in neurovascular gelatinolytic activity that was mediated by a fivefold increase in neutrophil-derived matrix metalloproteinase-9 (MMP-9) in the brains of IL-1 beta-challenged mice after MCAo. Specific inhibition of MMP-9 abrogated the effects of systemic inflammation on the sustained but not the acute disruption of claudin-5, which was associated with phosphorylation of cerebrovascular myosin light chain. MMP-9 inhibition also attenuated the deleterious impact of systemic inflammation on brain damage, edema, neurological deficit, and incidence of hemorrhagic transformation. These data indicate that a transformation from transient to sustained BBB disruption caused by enhanced neutrophil-derived neurovascular MMP-9 activity is a critical mechanism underlying the exacerbation of ischemic brain injury by systemic inflammation. These mechanisms may contribute to the poor clinical outcome in stroke patients presenting with antecedent infection.