Influence of intermittent hypoxia on the signal transduction pathways to inflammatory response and circadian clock regulation
Influence of intermittent hypoxia on the signal transduction pathways to inflammatory response and circadian clock regulation
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DOI：
10.1016/j.lfs.2009.07.002
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发表时间：
2009-08-26
期刊：
影响因子：
6.1
通讯作者：
Shimizu, Eiji
中科院分区：
文献类型：
--
作者：
Burioka, Naoto;Koyanagi, Satoru;Shimizu, Eiji
目的：阻塞性睡眠呼吸暂停综合征（OSAS），其特征是间歇性缺氧/复氧（IHR）。通常与循环炎症细胞因子水平的变化有关，并导致白天过度嗜睡、情绪紊乱和心血管疾病。在 OSAS 患者中观察到生物钟基因表达的节律异常，并且也与 OSAS 相关的临床症状有关。 IHR 诱导的信号转导被认为是 OSAS 相关并发症的基础。本研究的目的是阐明 IHR 对炎症反应和生物钟调节信号转导途径的影响。主要方法：为了评估 IHR 对细胞内信号传导的直接作用，我们使用细胞培养模型来探索 IHR 启动的潜在转录事件。主要发现：用 IHR 处理培养的人肺腺癌上皮细胞（A549），结果显示 炎症细胞因子白细胞介素 6 (IL-6) 的 mRNA 水平升高，这是由于核因子 kappa B（IL-6 的有效转录激活剂）信号通路的激活所致。另一方面，用 IHR 处理细胞对时钟基因响应元件驱动的转录几乎没有影响。因此，IHR 处理的细胞中时钟基因的 mRNA 水平没有显着变化。意义：这些结果表明 IHR 可以激活炎症反应的信号转导，但不能激活生物钟调节的信号转导。 OSAS 患者时钟基因表达的异常节律可归因于能够调节时钟基因表达的循环因子水平的变化。 (C) 2009 Elsevier Inc. 保留所有权利。
Aims: Obstructive sleep apnea syndrome (OSAS), characterized by intermittent hypoxia/reoxygenation (IHR). is often associated with changing levels of circulating inflammatory cytokines and causes excessive daytime sleepiness, mood disturbances, and cardiovascular disease. An abnormal rhythm in the expression of circadian clock genes is observed in OSAS patients, and is also implicated in OSAS-related clinical symptoms. IHR-induced signal transduction is thought to underlie OSAS-associated complications. The aim of this study is to elucidate the influence of IHR on signal transduction pathways to inflammatory response and circadian clock regulation.Main methods: To evaluate the direct action of IHR on intracellular signaling, we used a cell culture model to explore the underlying transcriptional events initiated by IHR.Key findings: Treatment of cultured human lung adenocarcinoma epithelial cells (A549) with IHR resulted in the elevation of mRNA levels of an inflammation cytokine interleukin-6 (IL-6), due to activation of the signaling pathway of nuclear factor-kappa B, a potent transcriptional activator of IL-6. On the other hand, the treatment of cells with IHR had little effect on clock gene response element-driven transcription. As a consequence, there was no significant change in mRNA levels of clock genes in IHR-treated cells.Significance: These results suggest that IHR can activate signal transduction to an inflammatory response, but not to circadian clock regulation. The abnormal rhythm in the expression of clock genes in OSAS patients is attributable to the changed levels of circulating factors that have the ability to modulate clock gene expression. (C) 2009 Elsevier Inc. All rights reserved.