A Critical Role for Fas/CD-95 Dependent Signaling Pathways in the Pathogenesis of Hyperoxia-Induced Brain Injury
A Critical Role for Fas/CD-95 Dependent Signaling Pathways in the Pathogenesis of Hyperoxia-Induced Brain Injury
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DOI：
10.1002/ana.21516
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发表时间：
2008-12-01
影响因子：
11.2
通讯作者：
Felderhoff-Mueser, Ursula
中科院分区：
文献类型：
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作者：
Dzietko, Mark;Boos, Vinzenz;Felderhoff-Mueser, Ursula
目的：早产儿在晚年有发生神经认知功能障碍的危险。氧气治疗最近被认为是发育中的啮齿动物大脑中神经元和少突胶质细胞凋亡的触发因素。方法：将6日龄Wistar大鼠暴露于80%氧气中2、6、12、24、48、72小时，同时将Fas(B6.MRL-Tnfrsft6(LPR))或Fas配体(B6Smn.C3-Fasl(GLD))缺陷小鼠和对照组(C57BL/6J)暴露于80%氧气中24小时。采用聚合酶链式反应、Western blotting和半胱氨酸天冬氨酸氨基转移酶(Caspase)活性测定。结果：Fas及其配体信使RNA和蛋白表达上调。此外，高氧诱导Fas下游信号转导事件，如Fas相关死亡结构域、FADD样白细胞介素1β转换酶抑制蛋白(Flip-L、Flip-S)的长短形式，以及caspase-8和caspase-3的裂解。在高氧开始时注射选择性caspase-8抑制剂(TRP801，1 mg/kg)可阻断该模型随后caspase-3的裂解。B6.MRL-Tnfrsf6(LPR)小鼠对氧介导的损伤具有保护作用，证实Fas参与了高氧诱导的细胞死亡。Fas配体缺乏的小鼠在细胞死亡数量上与对照组动物没有差异。解释：我们得出结论：新生儿高氧以Fas配体非依赖的方式触发Fas受体及其下游信号事件。功能Fas受体的缺乏和对caspase-8的选择性药物抑制阻止了caspase-3的激活，并提供了显著的神经保护作用。
Objective: Prematurely born infants are at risk for development of neurocognitive impairment in later life. Oxygen treatment has been recently identified as a trigger of neuronal and oligodendrocyte apoptosis in the developing rodent brain. We investigated the role of the Fas death receptor pathway in oxygen-triggered developmental brain injury.Methods: Six-day-old Wistar rats were exposed to 80% oxygen for various periods (2, 6, 12, 24, 48, and 72 hours), and mice deficient in either Fas (B6.MRL-Tnfrsft6(lpr)) or Fas ligand (B6Smn.C3-Fasl(gld)) and control mice (C57BL/6J) were exposed to 80% oxygen for 24 hours. Polymerase chain reaction, Western blotting, and caspase activity assays of thalamus and cortex tissue were performed.Results: Fas and Fas ligand messenger RNA and protein were upregulated. Furthermore, hyperoxia resulted in induction of downstream signaling events of Fas, such as Fas-associated death domain (FADD), the long and short form of FADD-like interleukin-1 beta-converting enzyme (FLICE) inhibitory protein (FLIP-L, FLIP-S), and cleavage of caspase-8 and caspase-3. Injection of a selective caspase-8 inhibitor (TRP801, 1mg/kg) at the beginning of hyperoxia blocked subsequent caspase-3 cleavage in this model. B6.MRL-Tnfrsf6(lpr) mice were protected against oxygen-mediated injury, confirming Fas involvement in hyperoxia-induced cell death. Mice deficient in Fas ligand did not differ from control animals in the amount of cell death.Interpretation: We conclude that neonatal hyperoxia triggers Fas receptor and its downstream signaling events in a Fas ligand-independent fashion. Lack of functional Fas receptors and selective pharmacological inhibition of caspase-8 prevents activation of caspase-3 and provides significant neuroprotection.