Central Mechanisms of Respiratory Arrest

描述（由申请人提供）：支气管肺C纤维（PCF）构成了来自肺部和气道的大部分传入神经，并在呼吸控制中发挥关键作用。肺部炎症和水肿刺激PCF，并经常伴有低氧血症。在这些病理条件下的患者中经常观察到通气不足和呼吸暂停，并且当睡眠中发生短暂的夜间低氧血症时会恶化甚至致命。然而，这些呼吸系统疾病的病理生理学尚不清楚。PCF刺激产生短暂的呼吸暂停，其通过释放谷氨酸作用于位于连合核（cNTS）附近的AMPA受体而中枢介导。巧合的是，通过激活也终止于cNTS的颈动脉体（CB）化学受体来提高吸气，并且其中一些化学受体在突触上会聚在由PCF驱动的神经元上。目前缺乏关于两种感觉输入之间的相互作用的信息，这两种感觉输入对会聚在同一中央结构中的解释驱动具有相反的影响。我们最近报道，PCF刺激急性缺氧期间产生的呼吸暂停（VA），16倍以上的PCF刺激单独诱导的呼吸暂停，提供了第一个证据来描述PCF激活和缺氧在控制呼吸的相互作用。在cNTS中给予的外源性P物质使PCF介导的呼吸暂停减少约10倍，CB刺激促进cNTS中的SP释放。因此，为了阐明潜在的VA的神经机制，我们将解决三个基本问题，在这个建议：（一）VA是否需要输入和相互作用发生外周和中枢？如果是，它们的相对贡献是什么？(b)中枢整合发生在哪里，涉及哪些神经递质？(c)中央相互作用是否发生在PCF驱动的神经元上，如果是的话，是如何发生的？我们的研究将提供一个更好的了解中央呼吸整合和呼吸系统疾病的病理生理学固有的疾病，涉及低氧血症和肺部炎症/水肿。

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.