Preconditioning suppresses inflammation in neonatal hypoxic ischemia via Akt activation
Preconditioning suppresses inflammation in neonatal hypoxic ischemia via Akt activation
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预处理通过 Akt 激活抑制新生儿缺氧缺血中的炎症
DOI：
10.1161/01.str.0000258102.18836.ca
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发表时间：
2007-03-01
期刊：
影响因子：
8.3
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Yin, Wei;Signore, Armando P.;Chen, Jun
背景和目的：低氧预适应(PC)对新生儿缺氧缺血性脑损伤(H-I)具有强大的神经保护作用，但其潜在机制尚不清楚。在成人大脑中，神经元缺血后的存活与磷脂酰肌醇3-激酶(PI3-K)/Akt信号通路的激活有关。抑制炎症是最近发现的PI3-K/Akt信号的直接结果。因此，我们研究了PI3-K/Akt是否具有抑制炎症和促进PC诱导的神经保护作用。方法出生后第7天的大鼠暴露于环境空气或8%氧气中3小时，以诱导缺氧性PC。24小时后，结扎一侧颈总动脉，低氧2.5小时，形成缺氧缺血模型。0~24小时后处死动物，检测Akt和糖原合成酶-3β磷酸化(p-Akt，p-GSK-3β)，24小时后测定细胞因子表达和炎性标志物，7天后测定脑组织丢失。另外，侧脑室注射LY294002以抑制PI3-K/Akt。PC能恢复p-Akt和Akt底物GSK-3β的水平，降低促炎标志物(核因子-kappa B、COX-2、CD68、髓过氧化物酶和小胶质细胞活化)，并明显改善脑缺血所致的脑组织损伤。用LY294002抑制PI3-K/Akt可减弱PC的神经保护作用，促进NF-kappa B、COX-2和CD68的表达。蛋白质组芯片分析显示，PC可抑制缺氧或一定剂量脂多糖诱导的促炎细胞因子的表达，从而使组织损伤最小。结论抑制炎症反应可能有助于PC对新生儿缺氧脑损伤的神经保护作用。这种作用部分是通过上调PI3-K/Akt活性来实现的。
Background and Purpose - Hypoxic preconditioning ( PC) confers robust neuroprotection against neonatal hypoxic-ischemic brain injury (H-I), yet the underlying mechanism is poorly understood. In the adult brain, neuronal survival after ischemia is associated with the activation of the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway. Suppression of inflammation is a newly identified direct consequence of PI3-K/Akt signaling. We therefore investigated whether PI3-K/Akt suppresses inflammation and contributes to PC-induced neuroprotection.Methods - Postnatal day 7 rats were exposed for 3 hours to either ambient air or 8% oxygen, which induces hypoxic PC. H-I was produced 24 hours later by unilateral carotid artery ligation followed by 2.5 hours of hypoxia. Animals were euthanized 0 to 24 hours later for detecting Akt and glycogen synthetase kinase-3 beta phosphorylation (p-Akt, p-GSK-3 beta), 24 hours later for assessing cytokine expression and inflammatory markers, and 7 days later for measuring brain tissue loss. In addition, LY294002 was injected intracerebroventricularly to inhibit PI3-K/Akt.Results - Brains with H-I without PC showed delayed but sustained reduction in p-Akt. PC restored the levels of p-Akt and the Akt substrate GSK-3 beta, reduced proinflammatory markers (NF-kappa B, COX-2, CD68, myeloperoxidase, and microglial activation), and markedly ameliorated H-I-induced brain tissue loss. Inhibition of PI3-K/Akt using LY294002 attenuated PC neuroprotection and promoted the expression of NF-kappa B, COX-2, and CD68. Proteomic microarray analysis revealed that PC inhibited expression of proinflammatory cytokines induced by H-I or a dose of lipopolysaccharide that resulted in minimal tissue damage.Conclusions - Suppression of inflammatory responses may contribute to PC neuroprotection against neonatal H-I brain injury. This effect is mediated in part via upregulating PI3-K/Akt activity.