Central Mechanisms of Respiratory Arrest

描述(申请人提供)：支气管肺C纤维(PCF)构成了来自肺和呼吸道的大多数传入神经，并在呼吸控制中发挥关键作用。肺部炎症和水肿会刺激PCF，并经常伴有低氧血症。在这些病理条件下，患者经常会出现低通气量和呼吸暂停，当睡眠中出现一过性夜间低氧血症时，这种情况会恶化，甚至是致命的。然而，这些呼吸系统疾病的病理生理学尚不清楚。刺激PCF产生短暂的呼吸暂停，这种呼吸暂停是通过释放谷氨酸作用于位于连合核(CNTs)附近的AMPA受体而起作用的。巧合的是，颈动脉小体(CB)化学受体的激活提高了灵感，这些受体也终止于碳纳米管，其中一些突触会聚在PCF驱动的神经元上。目前缺乏关于两种感觉输入之间相互作用的信息，这两种感觉输入在同一中枢结构中汇聚在一起，对呼吸驱动具有相反的影响。我们最近报道，在急性缺氧时刺激PCF会导致呼吸停止(VA)，是单独刺激PCF引起的呼吸暂停的16倍，这为描述PCF激活和低氧在呼吸控制中的相互作用提供了第一个证据。外源性P物质可延长PCF介导的呼吸暂停时间约10倍，CB刺激可促进CNT中SP的释放。因此，为了阐明VA背后的神经学机制，我们将在这一提议中解决三个基本问题：(A)VA是否既需要输入，又需要相互作用发生在外围和中枢？如果是，他们的相对贡献是什么？(B)中枢整合在哪里进行，涉及哪些神经递质？(C)中枢相互作用是否发生在PCF驱动的神经元上，如果是，是如何发生的？我们的研究将提供更好的了解中枢呼吸整合和呼吸系统疾病的病理生理学，包括低氧血症和肺部炎症/水肿症。

DESCRIPTION (provided by applicant): Bronchopulmonary C-fibers (PCFs) constitute the majority of afferent nerves arising from the lungs and airways and play a key role in respiratory control. Pulmonary inflammation and edema stimulate PCFs, and are frequently accompanied by hypoxemia. Hypoventilation and apnea are often observed in patients under these pathologic conditions and worsened or even fatal when transient nocturnal hypoxemia occurs in sleep. However, the pathophysiology of these respiratory disorders is unknown. PCF stimulation produces a brief apnea that is centrally mediated by releasing glutamate to act on AMPA receptors located in the vicinity of the commissural nucleus (cNTS). Coincidently, inspiration is elevated by activation of the carotid body (CB) chemo-receptors that also terminate in the cNTS and some of them synaptically converge on the neurons driven by PCFs. Information about the interaction between two sensory inputs with opposite effects on ventilatory drive converging in the same central structure is currently lacking. We recently reported that PCF stimulation during acute hypoxia produced a ventilatory arrest (VA), 16-fold longer than the apnea induced by PCF stimulation alone, providing first evidence to describe an interaction of PCF activation and hypoxia in the control of breathing. Exogenous Substance P administered in the cNTS prolongs PCF-mediated apnea by about 10-fold and CB stimulation promotes SP release in the cNTS. Therefore, to elucidate the neurologic mechanisms underlying the VA, we will address three fundamental questions in this proposal: (a) Does the VA require both inputs and the interaction occur peripherally and centrally? If so, what are their relative contributions? (b) Where does the central integration take place, and which neurotransmitters are involved? (c) Does the central interaction occur at PCF-driven neurons, and if so, how? Our study will provide a better understanding of central respiratory integration and the pathophysiology of respiratory disorders inherent in the diseases involving both hypoxemia and pulmonary inflammation/edema.