摘要
【研究背景】
呼吸是维持机体新陈代谢和功能活动所必须的基本生理过程，呼吸节律可因内、外环境的变化而发生改变。我们把机体为适应环境变化需要而发生的呼吸运动输出的改变称为呼吸可塑性。呼吸可塑性的异常可引起呼吸功能的障碍，如婴儿猝死综合症（sudden infant death syndrome，SIDS）和阻塞性睡眠呼吸暂停综合症（obstructive sleep apnea syndrome，OSAS）等。因为与疾病发生的密切关系，人们更加关注病理状态下呼吸可塑性的调控机制。到目前为止，长时程易化（long-term facilitation，LTF）模型是研究呼吸可塑性最常用的动物模型。LTF是指经过重复性的缺氧或药物干预后，诱导膈神经产生超出正常水平、持续增强长达1小时以上的高大放电效应。LTF的出现可以稳定上呼吸道并维持气道通畅，对睡眠呼吸紊乱疾病有潜在的治疗意义。
膈神经LTF（phrenic LTF，pLTF）在体情况下通常采用重复性缺氧来诱博士研究生：刘津平导师：刘莹莹鞠躬导，而在离体脑片培养模型中则采用间断性5-羟色胺(5-HT)灌流的方法来诱导。5-HT/5-HT2A受体(5-HT2AR)系统是LTF表达的必要条件，这一系统的异常往往导致呼吸紊乱的发生，然而对于5-HT系统激活后的细胞内信号转导途径还缺乏研究。在本研究中，我们通过低压氧仓间断性缺氧刺激模拟高海拔条件下的缺氧模式，建立了一个新的pLTF动物模型；另外，我们发现一次性系统给予外源性5-HT，可以兴奋膈神经放电并产生pLTF，这在以往研究中尚未有报导。应用我们构建的两种大鼠模型，结合药物干预实验，我们对pLTF的细胞内信号机制进行了研究。
【目的】
利用低压氧舱缺氧诱导和外源性5-HT诱导的pLTF模型，探讨5-HT→5-HT2AR→PKC通路在大鼠呼吸神经可塑性机制中的作用。
【方法】
(1)将大鼠置于密闭容器内，快速进行空气抽提，模拟9000～10000m高海拔环境，持续5分钟后，常氧通气5分钟，每日重复循环12小时，持续7天，进行慢性间断性缺氧(chronic intermittent hypoxia, CIH)预处理；第8天早晨给予3个循环的急性间断性缺氧(acute intermittent hypoxia, AIH)刺激，立即进行膈神经放电记录；(2)大鼠经腹腔麻醉后，切断双侧迷走神经，腹腔注射箭毒阻断自主呼吸，股动脉插管以便进行血气和血压监测，股静脉插管建立药物及液体通道。颈部分离右侧膈神经，给予药物或间断性缺氧刺激，记录膈神经放电情况。
【结果】
大鼠经低压氧舱CIH预处理后，AIH诱导的膈神经放电幅度较正常对照组（单纯AIH诱导）增高近一倍，缺氧30min、60min后仍然维持高大放电，形成增强的pLTF；静脉给予5-HT2AR拮抗剂ketanserin，可以部分阻断低压氧舱CIH诱导的pLTF，而静脉给予PKCθ抑制剂，不仅完全阻断pLTF的发生，而且影响了膈神经的规律性放电。
不同剂量5-HT对与膈神经放电的影响有所差异，但是基本都有短暂抑制现象的发生。20μg/kg仅引起了轻微的膈神经放电抑制，但很快恢复正常水平；40μg/kg对放电幅度和频率均有短暂抑制，但是仍较快恢复正常水平；100μg/kg的5-HT可引起先抑制后兴奋的双相膈神经放电，膈神经放电幅度较正常增高约30%并持续1小时以上，最终形成pLTF。静脉给予5-HT2AR拮抗剂ketanserin可完全阻断5-HT诱导的pLTF，而5-HT1AR拮抗剂WAY100635则没有作用。静脉注射PKC抑制剂staurosporine虽不影响初始抑制，但抑制了兴奋效应，完全阻断pLTF。我们还发现5-HT引起的双相放电依赖于两种相对独立的机制，其中初始抑制与结神经节相关，而后续的兴奋作用则与颈动脉体密切联系。摘除结神经节后，初始抑制消失，5-HT引起膈神经放电的增强，形成更加高大的pLTF，而摘除颈动脉体后，5-HT使抑制增强并延长，兴奋作用消失，pLTF无法形成。
【结论】
复杂的呼吸网络主要由连续性的感觉神经传入、中枢信号整合及膈神经的运动输出所构成，pLTF的表达无疑需要整个呼吸网络系统的激活。事实上，我们在本研究中揭示了一种由颈动脉体兴奋和结神经节抑制作用形成的外周动态平衡机制，而这种机制在5-HT诱导的pLTF中起关键作用。无论是在间断性低压氧舱诱导还是在5-HT诱导的pLTF大鼠模型中，我们的实验结果均表明5-HT→5-HT2AR→PKC信号通路对于pLTF形成的重要性。我们的研究将拓宽对于LTF发生机制的认识水平，并且为睡眠呼吸紊乱疾病的治疗提供潜在的可能性。
【Background】Respiration, a spontaneous rhythmic motor and one of the basiclife behaviors in maintaining body metabolism and function, varys with internaland external circumstances of each individual. The ability that alters respiratorymotor output to accommodate the ever-changing needs of the individual isregarded as respiratory plasticity. Failure of respiratory plasticity often leads tomalfunctions, such as sudden infant death syndrome and obstructive sleepapnea syndrome . Considering the tight relationship of respiratory plasticity withdiseases, people have paid much attention to the mechanism underlyingrespiratory plasticity, especially under pathological state. To date, the mostfrequently studied model of respiratory plasticity is long-term facilitation (LTF)model. LTF is a type of neuronal plasticity characterized by a progressiveincrease in phrenic nerve activity that lasts for at least one hour after stimuli(repetitive hypoxia, drug exposure, etc.), resulting in the increased pulmonaryventilation. LTF expression will help stabilize upper airways and maintain airwaypatency, implicating a potential clinical promise in treatment of sleep disorders.
Phrenic LTF (pLTF) is usually induced by repetitive hypoxia in vivo, orrepetitive 5-HT application in vitro slice preparation. 5-HT/5-HT2A receptor (5-HT2AR) system is necessary and sufficient for pLTF expression, andabnormalities of this system often lead to respiratory disorders. However, thedownstream intracellular signalings activated by 5-HT system are little known sofar. In the present study, we established a novel pLTF model through eposodichypobaric hypoxia to mimik a high-altitude hypoxic situation. Additionally, wefound that a bolus of systemic 5-HT admistration could exert the enhancedphrenic nerve activity and pLTF, which was proviously uncharacterized. Based onour established two pLTF models in combination with drugs’intervention, theunderlying intracellular signalings were then investigated in the present study.
【PurposPurpose】Using eposodic hypobaric- and 5-HT-induced pLTF models, we aimedto explore the roles of 5-HT→5-HT2AR→PKC pathway in respiratoryneuroplasticity in rats.
【Methods】(1) Rats were housed in a chamber and maintained alternately under 5min of hypobaric hypoxia and 5 min of normoxia between for 7 consecutive days.Hypobaric hypoxia was achieved by continuous air evacuation to gradually reacha high altitude of about 9000～10000 m. On the morning of the eighth day,phrenic nerve activity was recorded after three episodic hypoxia. (2) Animalswere anaesthetized intraperitoneally and subjected to bilateral midcervicalvagotomy and paralyzed with intraperitoneal injection of curarine to preventspontaneous breathing effort. A femoral arterial catheter was placed to allowblood sample withdrawal for blood gases and blood pressure measurement. Afemoral venous catheter was implanted for drugs and fluid administration. Theright phrenic nerve was isolated unilaterally and recorded after drugsadministration or episodic hypoxia.
【ResultResults】An augmented pLTF lasting for at least 60 min after AIH stimulus wasidentified in CIH-pretreated rats, which was almost doubled in comparison withcontrol animals (receiving AIH alone). Ketanserin, a selective 5-HT2ARantagonist, partly blocked the augmented pLTF induced by CIH. PKCθinhibitorcompletely blocked pLTF, and led to irregular patterns of phrenic nerve activity inCIH rats.
An immediate inhibition of phrenic nerve activity was consistentlydetectable in all animals with systemic 5-HT exposure, though the extent to whichdifferent doses of a bolus of 5-HT exerted was different. A bolus of 5-HTapplication at 20μg/kg dose elicited a slight inhibition of phrenic nerve activity,which returned to baseline immediately. 5-HT at 40μg/kg caused a transientinhibition in both the amplitude and the frequency. 5-HT at 100μg/kg dose gaverise to an immediate, marked inhibition and a subsequent striking facilitation ofphrenic nerve activity. The enhanced phrenic nerve activity could last for at least60 min after 5-HT pretreatment, representing the characteristic of pLTF.Ketanserin completely blocked 5-HT-induced pLTF, whereas WAY100635, aselective 5-HT1AR antagonist, didn’t work. PKC inhibitor, staurosporine, didn’taffect the initial inhibition induced by 5-HT, but substantially inhibited thesubsequent facilitation, leading to a complete blockage of pLTF. We then foundthat 5-HT-induced biphasic pattern formation and pLTF expression werecontributed by two separate mechanisms, the initial inhibition in association withthe nodose ganglion, and the subsequent brisk facilitation with the carotid body.Hence, 5-HT led to an enhanced pLTF when the initial inhibition was eliminatedwith bilateral nodose ganglionectomy. On the other hand, with bilateral carotidbody excision, the subsequent robust facilitation was abolished, and also the pLTF.
【Conclusions】Continuous sensory afferent inputs, central signal integration, and phrenic motor output constitute the complex respiratory network. pLTFexpression no doubt needs entire respiratory network activity. Indeed, the presentstudy unraveled a peripheral dynamic balance between carotid body excitationand nodose ganglion inhibition that contributed critically to 5-HT-induced pLTFexpression. 5-HT→5-HT2AR→PKC pathway plays an important role in pLTFformation, which is evident in both our established hypobaric- and 5-HT-inducedpLTF rat models. Our findings will extend our understanding of the mechanismundertaking LTF expression, and provide the potential likelihood for clinicaltreatment of sleep disorders.
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