Sustained exposure to cytokines and hypoxia enhances excitability of oxygen-sensitive type I cells in rat carotid body: correlation with the expression of HIF-1α protein and adrenomedullin.
Sustained exposure to cytokines and hypoxia enhances excitability of oxygen-sensitive type I cells in rat carotid body: correlation with the expression of HIF-1α protein and adrenomedullin.
复制标题
持续暴露于细胞因子和缺氧会增强大鼠颈动脉体氧敏感 I 型细胞的兴奋性：与 HIF-1α 蛋白和肾上腺髓质素表达的相关性。
DOI：
10.1089/ham.2012.1054
复制
发表时间：
2013
影响因子：
2.1
通讯作者：
Fidone,Salvatore
中科院分区：
文献类型：
--
作者：
Liu,Xuemei;He,Liang;Dinger,Bruce;Stensaas,Larry;Fidone,Salvatore
刘X.，L.He，B.Dinger，L.Stensaas，S.Fidone.持续暴露于细胞因子和低氧可增强大鼠颈动脉体氧敏感的I型细胞的兴奋性：与HIF-1α蛋白和肾上腺髓质素的表达相关。High Alt Med Biol14：53-60,2013。-我们实验室最近的研究表明，慢性低氧(CH)诱导大鼠颈动脉体局灶性炎症反应，其特征是巨噬细胞入侵和炎症细胞因子表达增加。此外，与常用抗炎药布洛芬和地塞米松同时治疗可阻断CH诱导的缺氧敏感性增加。本研究探讨了某些细胞因子增强颈动脉体氧敏感的I型细胞兴奋性的假说，以及细胞因子的下游效应涉及转录因子低氧诱导因子-1α(HIF-1α)的上调。培养的I型细胞暴露于缺氧和/或由白介素1β、白介素6和肿瘤坏死因子α组成的细胞因子的混合物中24 h。随后对低氧引起的细胞内钙离子反应的评估显示，先前暴露于细胞因子加低氧导致细胞兴奋性增加110%(p<；0.001)，而暴露于细胞因子或单独低氧引起的较小幅度的增加分别为22%(不显著)和35%(p<；0.01)。这些变化与类似处理的I型细胞中HIF-1α的免疫染色增加有关，在I型细胞中，暴露于细胞因子和低氧促进了转录因子的核转位。此外，细胞因子和/或低氧处理提高了HIF-1调节基因肾上腺髓质素的表达。这些体外实验结果得到了一些研究的支持，这些研究表明，与布洛芬同时治疗可以阻断活体CH后I型细胞敏感性的提高。这些数据表明，CH诱导动脉化学感受器的适应可能部分是通过细胞因子/低氧诱导HIF-1α上调，从而增强I型细胞中特定的低氧敏感基因的表达。
Liu, X., L. He, B. Dinger, L. Stensaas, and S. Fidone. Sustained exposure to cytokines and hypoxia enhances excitability of oxygen-sensitive type I cells in rat carotid body: Correlation with the expression of HIF-1α protein and adrenomedullin.High Alt Med Biol14:53–60, 2013.—Recent studies in our laboratory demonstrated that chronic hypoxia (CH) induces a localized inflammatory response in rat carotid body that is characterized by macrophage invasion and increased expression of inflammatory cytokines. Moreover, CH-induced increased hypoxic sensitivity is blocked by concurrent treatment with the common anti-inflammatory drugs, ibuprofen and dexamethasone. The present study examines the hypothesis that selected cytokines enhance the excitability of oxygen-sensitive type I cells in the carotid body, and that downstream effects of cytokines involve upregulation of the transcription factor, hypoxia inducible factor-1α (HIF-1α). Cultured type I cells were exposed for 24 h to hypoxia and/or a cocktail of cytokines consisting of interleukin-1β, interleukin-6, and tumor necrosis factor-α. Subsequent evaluation of hypoxia-evoked intracellular Ca2+-responses showed that previous exposure to cytokines plus hypoxia resulted in a 110% (p<0.001) increase in cell excitability, whereas exposure to cytokines or hypoxia alone elicited smaller increases of 22% (not significant) and 35% (p<0.01), respectively. These changes were correlated with increased immunostaining for HIF-1α in similarly treated type I cells, where exposure to cytokines plus hypoxia promoted the nuclear translocation of the transcription factor. Moreover, treatment with cytokines and/or hypoxia elevated the expression of the HIF-1-regulated gene, adrenomedullin. Thesein vitroresults are supported by studies which show that elevated type I cell sensitivity followingin vivoCH is blocked by concurrent treatment with ibuprofen. The data suggest that CH-induced adaptation in arterial chemoreceptors may in part be mediated by cytokine/hypoxia-induced upregulation of HIF-1α, and consequent enhanced expression of specific hypoxia-sensitive genes in type I cells.