Inflammatory mediators and modulation of blood-brain barrier permeability
Inflammatory mediators and modulation of blood-brain barrier permeability
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DOI：
10.1023/a:1007074420772
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发表时间：
2000-04-01
影响因子：
4
通讯作者：
Abbott, NJ
中科院分区：
文献类型：
--
作者：
Abbott, NJ
1. 与血液和神经系统之间的某些界面（如神经周围膜）不同，形成血脑屏障的脑内皮可以被一系列炎症介质调节。本文回顾了这种调节的机制，并讨论了对大脑治疗的影响。原位测量血脑屏障通透性的方法包括在实质血管中使用放射性标记示踪剂和测量跨内皮阻力和单头微血管荧光染料损失率。体外培养模型研究提供了所涉及的信号转导机制的细节。极性溶质穿过脑内皮的途径包括细胞旁紧密连接途径（通常非常紧密）和囊泡机制。据报道，炎症介质影响这两种通路，但最有力的证据是对紧密连接的调节。除了脑内皮细胞外，参与炎症反应的细胞类型还包括几种密切相关的细胞，包括周细胞、星形胶质细胞、平滑肌细胞、小胶质细胞、肥大细胞和神经元。在原位通常很难确定血管活性药物的作用部位。体外脑内皮模型在实验上更简单，但也可能缺乏细胞在原位产生的重要特征：细胞相互作用（如诱导、信号传导）。许多炎症因子增加了血管内皮的通透性和血管直径，共同导致血脑屏障的严重泄漏和脑水肿。这篇综述通过关注血管直径变化最小的研究来关注内皮通透性的变化。缓激素（Bk）(2)通过作用于B-2受体增加血脑屏障通透性。报道的下游事件包括[Ca2+]的升高(1)，磷脂酶A的激活(2)，花生四烯酸的释放和自由基的产生，有证据表明IL-1 β增强了Bk在缺血中的作用。在一些但不是全部的研究中，血清素（5HT）已被报道能增加血脑屏障的通透性。在看到屏障打开的地方，有证据表明5-HT2受体被激活，钙依赖性通透性增加。组胺是为数不多的中枢神经系统神经递质之一，可以引起持续的血脑屏障打开。早期文献尚不清楚，但对心脏血管和培养内皮的研究表明，H-2受体介导的通透性增加和[Ca2+]的升高(i)以及H-1受体介导的通透性降低与camp的升高有关。脑内皮细胞表达ATP、UTP和ADP的核苷酸受体，其激活引起血脑屏障通透性增加。该效应主要通过P-2 upsilon (P2Y(2)) g蛋白偶联受体介导，导致[Ca2+]升高(i)；P2Y(1)受体通过抑制腺苷酸环化酶而起作用，在一些体外制剂中有报道。花生四烯酸在某些神经疾病中升高，并导致血脑屏障向包括蛋白质在内的大分子开放。有证据表明花生四烯酸在代谢过程中通过环氧合酶和脂氧合酶途径产生自由基起作用。所描述的机制揭示了一系列相互关联的途径，通过这些途径，来自脑侧或血液侧的影响可以调节血脑屏障的通透性。对机制的了解已经被用于故意打开血脑屏障以向大脑输送药物，并且能够降低通透性的途径有望治疗炎症和脑水肿。
1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood-brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed.2. Methods for measuring blood-brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved.3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the dearest evidence is for modulation of tight junctions.4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling).5. Many inflammatory agents increase bath endothelial permeability and vessel diameter, together contributing to significant leak across the blood-brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized.6. Bradykinin (Bk)(2) increases blood-brain barrier permeability by acting on B-2 receptors. The downstream events reported include elevation of [Ca2+](i), activation of phospholipase A(2), release of arachidonic acid, and production of free radicals, with evidence that IL-1 beta potentiates the actions of Bk in ischemia.7. Serotonin (5HT) has been reported to increase blood-brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT2 receptors and a calcium-dependent permeability increase.8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood-brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H-2 receptors and elevation of [Ca2+](i) and an H-1 receptor-mediated reduction in permeability coupled to an elevation of cAMP.9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood-brain barrier permeability. The effects are mediated predominantly via a P-2 upsilon (P2Y(2)) G-protein-coupled receptor causing an elevation of [Ca2+](i); a P2Y(1) receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations.10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood-brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways.11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood-brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood-brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.