Expression of the Nrf2-system at the blood-CSF barrier is modulated by neonatal inflammation and hypoxia-ischemia
Expression of the Nrf2-system at the blood-CSF barrier is modulated by neonatal inflammation and hypoxia-ischemia
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DOI：
10.1007/s10545-012-9551-5
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发表时间：
2013-05-01
影响因子：
4.2
通讯作者：
Mallard, Carina
中科院分区：
文献类型：
--
作者：
D'Angelo, Barbara;Ek, C. Joakim;Mallard, Carina
转录因子NF-E2相关因子-2（Nrf 2）是内源性抗氧化系统的关键调节因子，通过保护血脑屏障功能在成人中发挥神经保护作用。脉络丛是血-CSF屏障的部位，已被认为在发育中维持脑屏障功能特别重要。我们研究了全身注射LPS、单侧脑缺氧缺血（HI）以及LPS和HI联合（LPS/HI）后脉络丛Nrf 2和解毒系统基因的表达。在9日龄小鼠中，在LPS、HI和LPS/HI后的不同时间点收集神经丛。通过定量PCR分析Nrf 2及其许多靶基因的mRNA水平。通过caspase-3免疫染色和TUNEL分析细胞死亡。LPS引起Nrf 2系统基因的下调，而HI在较早的时间点增加表达。HI前的LPS暴露阻止了许多HI诱导的基因增加。没有一种损伤导致脉络膜上皮细胞的任何明显死亡。这些数据表明，诱导抗氧化系统在脉络丛的功能是下调炎症，即使脉络膜细胞没有结构损伤。此外，LPS阻止了HI后的内源性抗氧化反应，表明如果LPS与增加氧化应激如缺氧缺血的损伤联合，脉络丛可能处于危险之中。
Transcription factor NF-E2-related factor-2 (Nrf2) is a key regulator of endogenous anti-oxidant systems shown to play a neuroprotective role in the adult by preserving blood-brain barrier function. The choroid plexus, site for the blood-CSF barrier, has been suggested to be particularly important in maintaining brain barrier function in development. We investigated the expression of Nrf2- and detoxification-system genes in choroid plexus following systemic LPS injections, unilateral cerebral hypoxia-ischemia (HI) as well as the combination of LPS and HI (LPS/HI). Plexuses were collected at different time points after LPS, HI and LPS/HI in 9-day old mice. mRNA levels of Nrf2 and many of its target genes were analyzed by quantitative PCR. Cell death was analyzed by caspase-3 immunostaining and TUNEL. LPS caused down-regulation of the Nrf2-system genes while HI increased expression at earlier time points. LPS exposure prior to HI prevented many of the HI-induced gene increases. None of the insults resulted in any apparent cell death to choroidal epithelium. These data imply that the function of the inducible anti-oxidant system in the choroid plexus is down-regulated by inflammation, even if choroid cells are not structurally damaged. Further, LPS prevented the endogenous antioxidant response following HI, suggesting the possibility that the choroid plexus may be at risk if LPS is united with an insult that increases oxidative stress such as hypoxia-ischemia.