Central Mechanisms of Respiratory Arrest

描述（由申请人提供）：支气管肺c -纤维（PCFs）构成了大部分来自肺部和气道的传入神经，在呼吸控制中起关键作用。肺部炎症和水肿刺激PCFs，并常伴有低氧血症。在这些病理条件下，患者经常观察到通气不足和呼吸暂停，当睡眠中发生一过性夜间低氧血症时，通气不足和呼吸暂停会恶化甚至致命。然而，这些呼吸系统疾病的病理生理机制尚不清楚。PCF刺激产生短暂的呼吸暂停，这是通过释放谷氨酸作用于交联核（cnt）附近的AMPA受体来中枢介导的。巧合的是，颈动脉小体（CB）化学受体的激活也会提高灵感，这些受体也终止于碳纳米管，其中一些会突触地聚集在由PCFs驱动的神经元上。关于两种感觉输入之间的相互作用，对通风驱动的相反影响汇聚在同一中央结构的信息目前缺乏。我们最近报道了急性缺氧时PCF刺激产生呼吸停止（VA），比单独PCF刺激引起的呼吸暂停时间长16倍，这为描述PCF激活和缺氧在呼吸控制中的相互作用提供了第一个证据。cNTS中外源性P物质可使pcf介导的呼吸暂停延长约10倍，而CB刺激可促进cNTS中SP的释放。因此，为了阐明VA的神经机制，我们将在本提案中解决三个基本问题：(a) VA是否同时需要输入和交互作用发生在周围和中心？如果有，他们的相对贡献是什么？(b)中枢整合在哪里发生，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？我们的研究将更好地理解中枢呼吸整合以及低氧血症和肺部炎症/水肿疾病中固有的呼吸系统疾病的病理生理学。

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.