Central Mechanisms of Respiratory Arrest

呼吸骤停的中枢机制

• 批准号: 6820060
• 负责人: Fadi Xu
• 金额: $ 37.83万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820060
• 关键词: C fiber; adenosine; apnea; hypoventilation; hypoxia; inflammation; laboratory rat; lactates; lung disorder; male; neurons; neuropathology; pathologic process; pulmonary edema; respiratory disorder; sleep apnea; substance P

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.

描述（由申请人提供）：支气管肺C纤维（PCF）构成由肺和气道引起的大多数传入神经，并在呼吸控制中起关键作用。肺部炎症和水肿刺激PCF，并且经常伴有低氧血症。在这些病理状况下，在患者中经常观察到过度衰减和呼吸暂停，当瞬时夜间低氧血症在睡眠中发生时，甚至致命。但是，这些呼吸系统疾病的病理生理尚不清楚。 PCF刺激会产生一个简短的呼吸暂停，该呼吸暂停是通过释放谷氨酸作用于位于合理核（CNTS）附近的AMPA受体作用的中心介导的。巧合的是，灵感通过激活颈动脉体（CB）化学受体的激活而提升，该化学疗法也终止在CNT中，其中一些是在PCF驱动的神经元上的突触收敛。目前缺乏有关两个感官输入之间对通气驱动器融合的相反影响的感觉输入之间相互作用的信息。我们最近报道说，急性缺氧期间的PCF刺激产生了通气停滞（VA），仅在PCF刺激中诱导的呼吸暂停长16倍，提供了第一个证据，以描述PCF激活和缺氧在控制呼吸方面的相互作用。在CNT中施用的外源物质P可将PCF介导的呼吸暂停延长约10倍，而CB刺激促进了CNT中的SP释放。因此，为了阐明VA的神经系统机制，我们将在此提案中解决三个基本问题：（a）VA是否需要投入，并且相互作用在周围和集中发生？如果是这样，他们的相对贡献是什么？ （b）中央集成在哪里进行，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，如何？我们的研究将更好地理解中枢呼吸道整合以及涉及低氧血症和肺部炎症/水肿的疾病固有的呼吸疾病的病理生理学。