Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome
Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome
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DOI：
10.1161/circulationaha.105.556746
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发表时间：
2005-10-25
期刊：
影响因子：
37.8
通讯作者：
McNicholas, WT
中科院分区：
文献类型：
--
作者：
Ryan, S;Taylor, CT;McNicholas, WT
背景-阻塞性睡眠呼吸暂停综合征(OSAS)以间歇性低氧/复氧(IHR)为特征，是心血管疾病的独立危险因素。方法和结果：在一种新的IHR体外模型中，我们使用转染有报告结构的HeLa细胞和DNA结合分析来研究IHR重复暴露所引发的潜在转录事件。此外，我们前瞻性地研究了19名男性OSAS患者(中位呼吸暂停-低通气频率，每小时48.5次；四分位数范围[IQR]，28.5至72.9)和17名匹配的正常对照组受试者。所有受试者在基线和持续气道正压治疗6周后检测促炎症细胞因子肿瘤坏死因子-α和适应性因子促红细胞生成素的循环水平。作为详细基线评估的一部分，对全血计数进行了测量。荧光素酶报告分析和DNA结合研究表明，暴露于IHR的HeLa细胞显示前炎症转录因子NF-kappa B(P<；0.001)被选择性激活，而适应性调节因子HIF-1不被激活。OSAS患者外周血肿瘤坏死因子-α水平(2.56pg/mL；IQR2.01~3.42pg/mL)高于对照组(1.25pg/mL；IQR0.94~1.87；P<；0.001)，但经持续气道正压治疗后恢复正常(1.24pg/mL；IQR0.78~2.35pg/mL，P=0.002)。相比之下，促红细胞生成素水平在整个过程中都是相似的。此外，OSAS患者外周血中中性粒细胞水平高于对照组，而红细胞压积无明显变化。结论--这些数据表明，在IHR和OSAS患者中，炎症的选择性激活超越了适应性途径，这可能是心血管疾病的重要分子机制。
Background-Obstructive sleep apnea syndrome (OSAS), characterized by intermittent hypoxia/reoxygenation (IHR), is an independent risk factor for cardiovascular disease. We investigated the underlying molecular mechanisms of this association in a translational study.Methods and Results-In a novel in vitro model of IHR, we used HeLa cells transfected with reporter constructs and DNA binding assays for the master transcriptional regulators of the inflammatory and adaptive pathways (NF kappa B and HIF-1, respectively) to investigate underlying transcriptional events initiated by repeated cell exposure to IHR. Furthermore, we prospectively studied 19 male OSAS patients ( median apnea-hypopnea frequency, 48.5 episodes per hour; interquartile range [IQR], 28.5 to 72.9) and 17 matched normal control subjects. Circulating levels of the proinflammatory cytokine tumor necrosis factor-alpha and the adaptive factor erythropoietin were assayed in all subjects at baseline and again after 6 weeks of continuous positive airway pressure therapy in patients. Full blood count was measured as part of a detailed baseline evaluation. HeLa cells exposed to IHR demonstrated selective activation of the proinflammatory transcription factor NF kappa B ( P < 0.001 by ANOVA), whereas the adaptive regulator HIF-1 was not activated, as demonstrated by luciferase reporter assays and DNA binding studies. Circulating tumor necrosis factor-alpha levels were higher in OSAS patients (2.56 pg/ mL; IQR, 2.01 to 3.42 pg/ mL) than in control subjects (1.25 pg/ mL; IQR, 0.94 to 1.87; P < 0.001) but normalized with continuous positive airway pressure therapy (1.24 pg/ mL; IQR, 0.78 to 2.35 pg/ mL; P = 0.002). In contrast, erythropoietin levels were similar throughout. Furthermore, circulating neutrophil levels were higher in OSAS patients than in control subjects, whereas the hematocrit was unaltered.Conclusions-These data demonstrate selective activation of inflammatory over adaptive pathways in IHR and OSAS, which may be an important molecular mechanism of cardiovascular disease.