Yang Chang-Huan, Zhuang Wei-Ling, Shen Yan-Jhih, Lai Ching Jung, Kou Yu Ru
School of Medicine, Institute of Physiology, National Yang-Ming University Taipei, Taiwan.
Department of Physiology, Tzu Chi University Hualien, Taiwan.
Front Physiol. 2016 May 9;7:166. doi: 10.3389/fphys.2016.00166. eCollection 2016.
Obstructive sleep apnea (OSA), manifested by exposure to chronic intermittent hypoxia (CIH) and excess production of reactive oxygen species (ROS) in the airways, is associated with hyperreactive airway diseases. ROS, particularly when created by NADPH oxidase, are known to sensitize lung vagal C fibers (LVCFs), which may contribute to airway hypersensitivity pathogenesis. We investigated whether CIH augments the reflex and afferent responses of LVCFs to chemical stimulants and the roles of ROS and NADPH oxidase in such airway hypersensitivity. Rats were exposed to room air (RA) or CIH with/without daily treatment with MnTMPyP (a superoxide anion scavenger), apocynin (an NADPH oxidase inhibitor), or vehicle. At 16 h after their last exposure, intravenous capsaicin, adenosine, or α,β-methylene-ATP evoked an augmented apneic response in anesthetized rats with 14-days CIH exposure, compared to anesthetized rats with 14-days RA exposure. The augmented apneic responses to these LVCF stimulants were abolished by bilateral vagotomy or perivagal capsaicin treatment, which block LVCFs neural conduction and were significantly suppressed by treatment with MnTMPyP or apocynin, but not vehicle. Electrophysiological studies revealed that 14-days CIH exposure potentiated the responses of LVCFs to these stimulants. This effect was inhibited by treatment with MnTMPyP or apocynin treatment and was not seen in rats who received 7-days of CIH exposure. Biochemical analysis indicated that 14-days CIH exposure increased both lung lipid peroxidation, which is indicative of oxidative stress, and expression of the p47(phox) subunit in the membrane fraction of lung tissue, which is an index of NADPH oxidase activation. The former was prevented by treatment with either MnTMPyP or apocynin, while the later was prevented by treatment with apocynin only. These results suggest that 14-days CIH exposure sensitizes LVCFs in rats, leading to an exaggerated reflex and afferent responses to stimulants and that this sensitization is mediated via ROS generated by NADPH oxidase.
阻塞性睡眠呼吸暂停(OSA)表现为暴露于慢性间歇性缺氧(CIH)以及气道中活性氧(ROS)的过量产生,与气道高反应性疾病相关。已知ROS,特别是由NADPH氧化酶产生时,会使肺迷走神经C纤维(LVCF)敏感化,这可能有助于气道高敏反应的发病机制。我们研究了CIH是否会增强LVCF对化学刺激物的反射和传入反应,以及ROS和NADPH氧化酶在这种气道高敏反应中的作用。将大鼠暴露于室内空气(RA)或CIH环境中,并每日给予/不给予MnTMPyP(一种超氧阴离子清除剂)、阿朴吗啡(一种NADPH氧化酶抑制剂)或赋形剂治疗。在最后一次暴露后16小时,与暴露于14天RA的麻醉大鼠相比,静脉注射辣椒素、腺苷或α,β-亚甲基-ATP在暴露于14天CIH的麻醉大鼠中引起增强的呼吸暂停反应。对这些LVCF刺激物增强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治疗被消除,这两种方法可阻断LVCF的神经传导,并且用MnTMPyP或阿朴吗啡治疗可显著抑制,但用赋形剂治疗则无此效果。电生理研究表明,暴露于14天CIH会增强LVCF对这些刺激物的反应。这种效应被MnTMPyP或阿朴吗啡治疗所抑制,而在暴露于7天CIH的大鼠中未观察到。生化分析表明,暴露于14天CIH会增加肺脂质过氧化(这是氧化应激的指标)以及肺组织膜部分中p47(phox)亚基的表达(这是NADPH氧化酶激活的指标)。前者可通过用MnTMPyP或阿朴吗啡治疗来预防,而后者仅可通过用阿朴吗啡治疗来预防。这些结果表明,暴露于14天CIH会使大鼠的LVCF敏感化,导致对刺激物的反射和传入反应过度增强,并且这种敏感化是通过NADPH氧化酶产生的ROS介导的。