Huang Ya-Chen, Yuan Zung Fan, Yang Chang-Huan, Shen Yan-Jhih, Lin Jyun-Yi, Lai Ching Jung
Department of Chest Section, Buddhist Tzu Chi General Hospital, Hualien City, Taiwan.
Master Program in Physiological and Anatomical Medicine, School of Medicine, Tzu Chi University, Hualien City, Taiwan.
Front Physiol. 2018 Jul 5;9:847. doi: 10.3389/fphys.2018.00847. eCollection 2018.
Obstructive sleep apnea is mainly characterized by intermittent hypoxia (IH), which is associated with hyperreactive airway diseases and lung inflammation. Sensitization of lung vagal C fibers (LVCFs) induced by inflammatory mediators may play a central role in the pathogenesis of airway hypersensitivity. In females, estrogen interferes with inflammatory signaling pathways that may modulate airway hyperreactivity. In this study, we investigated the effects of IH on the reflex and afferent responses of LVCFs to chemical stimulants and lung inflammation in adult female rats, as well as the role of estrogen in these responses. Intact and ovariectomized (OVX) female rats were exposed to room air (RA) or IH for 14 consecutive days. On day 15, IH enhanced apneic responses to right atrial injection of chemical stimulants of LVCFs (e.g., capsaicin, phenylbiguanide, and α,β-methylene-ATP) in intact anesthetized females. Rats subjected to OVX prior to IH exposure exhibited an augmented apneic response to the same dose of stimulants compared with rats subjected to other treatments. Apneic responses to the stimulants were completely abrogated by bilateral vagotomy or perivagal capsaicin treatment, which blocked the neural conduction of LVCFs. Electrophysiological experiments revealed that in IH-exposed rats, OVX potentiated the excitability of LVCFs to stimulants. Moreover, LVCF hypersensitivity in rats subjected to OVX prior to IH exposure was accompanied by enhanced lung inflammation, which was reflected by elevated inflammatory cell infiltration in bronchoalveolar lavage fluid, lung lipid peroxidation, and protein expression of inflammatory cytokines. Supplementation with 17β-estradiol (E2) at a low concentration (30 μg/ml) but not at high concentrations (50 and 150 μg/ml) prevented the augmenting effects of OVX on LVCF sensitivity and lung inflammation caused by IH. These results suggest that ovarian hormones prevent the enhancement of LVCF sensitivity and lung inflammation by IH in female rats, which are related to the effect of low-dose estrogen.
阻塞性睡眠呼吸暂停主要特征为间歇性缺氧（IH），其与气道高反应性疾病和肺部炎症相关。炎症介质诱导的肺迷走神经C纤维（LVCFs）致敏可能在气道高敏反应的发病机制中起核心作用。在雌性中，雌激素干扰可能调节气道高反应性的炎症信号通路。在本研究中，我们调查了IH对成年雌性大鼠LVCFs对化学刺激物的反射和传入反应以及肺部炎症的影响，以及雌激素在这些反应中的作用。完整和卵巢切除（OVX）的雌性大鼠连续14天暴露于室内空气（RA）或IH。在第15天，IH增强了完整麻醉雌性大鼠中LVCFs对右心房注射化学刺激物（如辣椒素、苯乙双胍和α,β-亚甲基-ATP）的呼吸暂停反应。在IH暴露前接受OVX的大鼠与接受其他处理的大鼠相比，对相同剂量刺激物的呼吸暂停反应增强。对刺激物的呼吸暂停反应通过双侧迷走神经切断术或迷走神经周围辣椒素处理完全消除，这阻断了LVCFs的神经传导。电生理实验表明，在IH暴露的大鼠中，OVX增强了LVCFs对刺激物的兴奋性。此外，在IH暴露前接受OVX的大鼠中LVCF超敏反应伴有肺部炎症增强，这通过支气管肺泡灌洗液中炎症细胞浸润增加、肺脂质过氧化和炎症细胞因子的蛋白表达来反映。低浓度（30μg/ml）而非高浓度（50和150μg/ml）补充17β-雌二醇（E2）可防止OVX对IH引起的LVCF敏感性和肺部炎症的增强作用。这些结果表明，卵巢激素可防止IH增强雌性大鼠的LVCF敏感性和肺部炎症，这与低剂量雌激素的作用有关。
