Sunderram Jag, Semmlow John, Patel Pranav, Rao Harshit, Chun Glen, Agarwala Priya, Bhaumik Mantu, Le-Hoang Oanh, Lu Shou-En, Neubauer Judith A
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey;
Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.
J Appl Physiol (1985). 2016 Oct 1;121(4):944-952. doi: 10.1152/japplphysiol.00036.2016. Epub 2016 Sep 8.
Chronic intermittent hypoxia (CIH) increases sympathetic tone and respiratory instability. Our previous work showed that chronic hypoxia induces the oxygen-sensing enzyme heme oxygenase-1 (HO-1) within the C1 sympathoexcitatory region and the pre-Bötzinger complex (pre-BötC). We therefore examined the effect of CIH on time course of induced expression of HO-1 within these regions and determined whether the induction of HO-1 correlated with changes in respiratory, sigh frequency, and sympathetic responses (spectral analysis of heart rate) to acute hypoxia (10% O) during 10 days of exposure to CIH in chronically instrumented awake wild-type (WT) and HO-1 null mice (HO-1). HO-1 was induced within the C1 and pre-BötC regions after 1 day of CIH. There were no significant differences in the baseline respiratory parameters between WT and HO-1 Prior to CIH, acute hypoxia increased respiratory frequency in both WT and HO-1; however, minute diaphragm electromyogram activity increased in WT but not HO-1 The hypoxic respiratory response after 1 and 10 days of CIH was restored in HO-1 CIH resulted in an initial significant decline in 1) the hypoxic sigh frequency response, which was restored in WT but not HO-1, and 2) the baseline sympathetic activity in WT and HO-1, which remained stable subsequently in WT but not in HO-1 We conclude that 1) CIH induces expression of HO-1 in the C1 and pre-BötC regions within 1 day and 2) HO-1 is necessary for hypoxia respiratory response and contributes to the maintenance of the hypoxic sigh responses and baseline sympathetic activity during CIH.
慢性间歇性缺氧（CIH）会增加交感神经张力和呼吸不稳定性。我们之前的研究表明，慢性缺氧会在C1交感神经兴奋区域和前包钦格复合体（pre-BötC）内诱导氧敏感酶血红素加氧酶-1（HO-1）的产生。因此，我们研究了CIH对这些区域内HO-1诱导表达时间进程的影响，并确定HO-1的诱导是否与在慢性植入仪器的清醒野生型（WT）小鼠和HO-1基因敲除小鼠（HO-1）暴露于CIH的10天期间，对急性缺氧（10%氧气）的呼吸、叹息频率和交感神经反应（心率频谱分析）的变化相关。CIH处理1天后，C1和pre-BötC区域内诱导产生了HO-1。WT和HO-1之间的基线呼吸参数没有显著差异。在CIH之前，急性缺氧使WT和HO-1的呼吸频率均增加；然而，WT的膈膜肌电图活动分钟数增加，而HO-1没有。HO-1基因敲除小鼠在CIH处理1天和10天后的低氧呼吸反应得以恢复。CIH导致1）低氧叹息频率反应最初显著下降，WT可恢复而HO-1不能，以及2）WT和HO-1的基线交感神经活动最初显著下降，随后WT保持稳定而HO-1没有。我们得出结论：1）CIH在1天内诱导C1和pre-BötC区域内HO-1的表达；2）HO-1对于低氧呼吸反应是必需的，并且有助于在CIH期间维持低氧叹息反应和基线交感神经活动。
