School of Medicine and Medical Science, The Conway Institute, University College Dublin, Ireland.
School of Medicine and Medical Science, The Conway Institute, University College Dublin, Ireland; Pulmonary and Sleep Disorders Unit, St. Vincent's University Hospital, Dublin, Ireland.
Biochem Biophys Res Commun. 2014 May 16;447(4):660-5. doi: 10.1016/j.bbrc.2014.04.062. Epub 2014 Apr 19.
Intermittent hypoxia (IH)-induced activation of pro-inflammatory pathways is a major contributing factor to the cardiovascular pathophysiology associated with obstructive sleep apnea (OSA). Obesity is commonly associated with OSA although it remains unknown whether adipose tissue is a major source of inflammatory mediators in response to IH. The aim of this study was to test the hypothesis that IH leads to augmented inflammatory responses in human adipocytes when compared to cells of non-adipocyte lineages.
Human primary subcutaneous and visceral adipocytes, human primary microvascular pulmonary endothelial cells (HUMEC-L) and human primary small airway epithelial cells (SAEC) were exposed to 0, 6 or 12 cycles of IH or stimulated with tumor necrosis factor (TNF)-α. IH led to a robust increase in NF-κB DNA-binding activity in adipocytes compared with normoxic controls regardless of whether the source of adipocytes was visceral or subcutaneous. Notably, the NF-κB response of adipocytes to both IH and TNF-α was significantly greater than that in HUMEC-L and SAEC. Western blotting confirmed enhanced nuclear translocation of p65 in adipocytes in response to IH, accompanied by phosphorylation of I-κB. Parallel to p65 activation, we observed a significant increase in secretion of the adipokines interleukin (IL)-8, IL-6 and TNF-α with IH in adipocytes accompanied by significant upregulation of mRNA expression. PCR-array suggested profound influence of IH on pro-inflammatory gene expression in adipocytes.
Human adipocytes demonstrate strong sensitivity to inflammatory gene expression in response to acute IH and hence, adipose tissue may be a key source of inflammatory mediators in OSA.
间歇性低氧（IH）诱导的促炎途径激活是与阻塞性睡眠呼吸暂停（OSA）相关的心血管病理生理学的主要因素。肥胖症通常与 OSA 相关，但尚不清楚脂肪组织是否是对 IH 产生炎症介质的主要来源。本研究旨在检验以下假设，即与非脂肪细胞谱系的细胞相比，IH 会导致人脂肪细胞中炎症反应增强。
将人原代皮下和内脏脂肪细胞、人原代肺微血管内皮细胞（HUMEC-L）和人原代小气道上皮细胞（SAEC）暴露于 0、6 或 12 个 IH 循环或用肿瘤坏死因子（TNF）-α刺激。与常氧对照相比，IH 导致脂肪细胞中 NF-κB DNA 结合活性明显增加，而与脂肪细胞的来源是内脏还是皮下无关。值得注意的是，脂肪细胞对 IH 和 TNF-α的 NF-κB 反应均明显大于 HUMEC-L 和 SAEC。Western blot 证实，IH 可增强脂肪细胞中 p65 的核易位，并伴有 I-κB 的磷酸化。与 p65 激活平行，我们观察到 IH 可使脂肪细胞中白细胞介素（IL）-8、IL-6 和 TNF-α等脂肪因子的分泌显著增加，同时伴有 mRNA 表达的显著上调。PCR 阵列表明 IH 对脂肪细胞中促炎基因表达有深远影响。
人脂肪细胞对急性 IH 诱导的炎症基因表达具有很强的敏感性，因此，脂肪组织可能是 OSA 中炎症介质的主要来源。
