BHF Centre of Research Excellence, Cardiovascular Division, King's College London, London SE1 9NH, UK.
Free Radic Biol Med. 2011 Feb 15;50(4):518-24. doi: 10.1016/j.freeradbiomed.2010.12.010. Epub 2010 Dec 16.
Free radical generation is a key event in cerebral reperfusion injury. Bradykinin (Bk) and interleukin-1β (IL-1β) have both been implicated in edema formation after stroke, although acute Bk application itself results in only a modest permeability increase. We have investigated the molecular mechanism by assessing the permeability of single pial venules in a stroke model. Increased permeability on reperfusion was dependent on the duration of ischemia and was prevented by applying the B(2) receptor antagonist HOE 140. Postreperfusion permeability increases were mimicked by applying Bk (5μM) for 10 min and blocked by coapplying the IL-1 receptor antagonist with Bk. Furthermore, 10 min pretreatment with IL-1β resulted in a 3 orders of magnitude leftward shift of the acutely applied Bk concentration-response curve. The left shift was abolished by scavenging free radicals with superoxide dismutase and catalase. Apocynin coapplied with IL-1β completely blocked the potentiation, implying that NADPH oxidase assembly is the immediate target of IL-1β. In conclusion, this is first demonstration that bradykinin, released during cerebral ischemia, leads to IL-1β release, which in turn activates NADPH oxidase leading to blood-brain barrier breakdown.
自由基的产生是脑再灌注损伤的关键事件。缓激肽（Bk）和白细胞介素-1β（IL-1β）都与中风后水肿的形成有关，尽管急性 Bk 应用本身只会导致轻微的通透性增加。我们通过评估中风模型中单脑膜小静脉的通透性来研究分子机制。再灌注时通透性的增加取决于缺血的持续时间，应用 B(2)受体拮抗剂 HOE 140 可预防。Bk（5μM）作用 10 分钟可模拟再灌注后的通透性增加，并且与 Bk 共同应用 IL-1 受体拮抗剂可阻断这种增加。此外，用 IL-1β预处理 10 分钟会导致急性应用 Bk 的浓度-反应曲线向左移动 3 个数量级。用超氧化物歧化酶和过氧化氢酶清除自由基可消除这种左移。阿朴肉桂酸与 IL-1β 共同应用可完全阻断这种增强作用，这表明 NADPH 氧化酶的组装是 IL-1β 的直接靶标。总之，这首次证明了缓激肽在脑缺血期间释放，导致白细胞介素-1β 的释放，而白细胞介素-1β 又激活 NADPH 氧化酶导致血脑屏障破裂。
