Effect of lipopolysaccharide on global gene expression in the immature rat brain
Effect of lipopolysaccharide on global gene expression in the immature rat brain
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DOI：
10.1203/01.pdr.0000228323.32445.7d
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发表时间：
2006-08-01
影响因子：
3.6
通讯作者：
Mallard, Carina
中科院分区：
文献类型：
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作者：
Eklind, Saskia;Hagberg, Henrik;Mallard, Carina
为了进一步了解脂多糖（LPS）影响未成熟大脑的分子机制，研究了新生大鼠LPS暴露后的整体基因表达。在LPS后2、6和72小时取样大脑（n = 5/时间点），并与年龄匹配的对照组进行比较。分别在Affymextrix基因芯片大鼠表达集230上分析各脑mRNA。LPS处理后的基因数量在2小时为847个，6小时为1564个，72小时为1546个。基因本体分析表明，在LPS处理后的2和6小时，与蛋白质代谢、对外部刺激和应激反应（免疫和炎症反应、趋化性）和细胞死亡相关的基因被过度表达。在72 h时，受调控最强烈的基因属于神经递质的分泌、运输、突触传递、细胞迁移和神经发生。确定了与细胞死亡/存活相关的几种途径（caspase-tumor necrosis factor - α [tnf - α]-、p53-和Akt/磷脂酰肌醇-3激酶（PI3K）依赖机制）。外周LPS暴露8 h后，Caspase-3活性升高，Akt磷酸化降低。这些结果表明，大脑对外周LPS暴露有复杂的反应。除了炎症反应外，还发现了大量细胞死亡相关基因，这可能导致LPS暴露后未成熟大脑对缺氧缺血（HI）的易感性增加。
To improve the understanding of the molecular mechanisms whereby lipopolysaccharide (LPS) affects the immature brain, global gene expression following LPS exposure was investigated in neonatal rats. Brains (n = 5/time point) were sampled 2, 6, and 72 h after LPS and compared with age-matched controls. The mRNA from each brain was analyzed separately on Affymextrix GeneChip Rat Expression Set 230. The number of genes regulated after LPS were 847 at 2 h, 1564 at 6 h, and 1546 genes at 72 h. Gene ontology analysis demonstrated that, at both 2 and 6 h after LPS, genes associated with protein metabolism, response to external stimuli and stress (immune and inflammatory response, chemotaxis) and cell death were overrepresented. At 72 h, the most strongly regulated genes belonged to secretion of neurotransmitters, transport, synaptic transmission, cell migration, and neurogenesis. Several pathways associated with cell death/survival were identified (caspase-tumor necrosis factor alpha [TNF-alpha]-, p53-, and Akt/phosphatidylinositol-3-kinase (PI3K)-dependent mechanisms). Caspase-3 activity increased and phosphorylation of Akt decreased 8 h after peripheral LPS exposure. These results show a complex cerebral response to peripheral LPS exposure. In addition to the inflammatory response, a significant number of cell death-associated genes were identified, which may contribute to increased vulnerability of the immature brain to hypoxia-ischemia (HI) following LPS exposure.