Effect of Prenatal Nicotinic Exposure on Control of Hypoxic Ventilatory Response

产前烟碱暴露对控制缺氧通气反应的影响

• 批准号: 8449130
• 负责人: Fadi Xu
• 金额: $ 39.14万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449130
• 关键词: AMPA Receptors; Abbreviations; Acids; Acute; Adenosine; Animal Model; Apnea; Blood gas; Bradycardia; Breathing; C Fiber; Capsaicin; Carotid Body; Cells; Cervical; Cessation of life; Data; Depressed mood; Development; Disease; Environmental air flow; Event; Failure; Female; Functional disorder; Glutamates; Hypoxemia; Hypoxia; Infant; Infant Mortality; Knowledge; Label; Lactation; Lead; Lesion; Life; Mediating; Modeling; Molecular; Neurons; Nicotine; Nucleus solitarius; Pathogenesis; Patients; Peripheral; Pilot Projects; Play; Pneumonia; Population; Pregnancy; Prevention strategy; Purinergic P1 Receptors; Radioimmunoassay; Rattus; Respiration Disorders; Respiratory Failure; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Sex Characteristics; Substance P; Substance P Receptor; Sudden Death; Sudden infant death syndrome; Synapses; Testing; cigarette smoking; cigarette smoking; density; extracellular; improved; insight; male; mortality; perineural; postnatal; prenatal; prevent; public health relevance; pup; receptor; receptor expression; respiratory; response

DESCRIPTION (provided by applicant): Sudden infant death syndrome (SIDS) is a leading cause of infant mortality. Cigarette smoke (nicotinic exposure) is the key risk factor and hypoxemia is an acute precursor for SIDS. Although the pathogenic mechanisms of SIDS are poorly understood, a depressed hypoxic ventilatory response (dHVR) has been assumed to be a major player. An existing SIDS animal model induced by traditional prenatal nicotinic exposure (tPNE) has shown an excessive mortality (15%) during 60 min severe hypoxia in rat pups. Aim 1 of this project is to improve this model by using a more realistic "full-term" PNE (fPNE) that consists of the period before pregnancy and during pregnancy and lactation to maximize adverse impacts of PNE on cardiorespiratory functions. In addition, the causal role of the dHVR in the mortality and the central origin of the dHVR will be further defined. Recently, we found that inactivation of bronchopulmonary C-firers (PCFs) uniquely eliminated the dHVR observed in rats with pulmonary inflammation, suggesting a critical role of PCFs in blunting the HVR under pathological condition. PCFs are reportedly sensitized by cigarette smoke (nicotine) and stimulated by the hypoxic product adenosine (AD) mainly via acting on A1 receptor (A1R). These findings, along with increased vagal C-fibers in SIDS victims, lead to Aim 2, in which we will determine if fPNE-induced dHVR and death depend on AD stimulating PCFs and if fPNE amplifies the PCF response to hypoxia (AD) mainly via increasing PCFs' population and A1Rs in our model. It is generally accepted that activation of PCFs inhibits ventilation via releasing glutamate that stimulates PCF-driven neurons in the caudal and middle nucleus tractus solitarius (mNTS) via acting on AMPA receptor (AMPAR). This inhibition is amplified by local substance P (SP) acting on neurokinin 1 receptor (NK1R). Most importantly, local SP release is mediated by hypoxic stimulation of the carotid body and is greatly elevated in SIDS victims. Because fPNE upregulates mNTS NK1R expression in our pilot data, studies in Aim 3 will define if fPNE promotes NK1R and SP synthesis and the hypoxia-induced SP release in the mNTS to centrally augment PCF-driven neuronal activity via SP facilitating AMPAR-mediated neuronal activity, leading to the dHVR. The proposed studies will be performed in rat pups by using electrophysiological, pharmacological, immunocytochemical, and molecular approaches. Our predicted results as described in the aims will: 1) generate a new concept of PCFs' plasticity and PCFs' role in control of breathing during postnatal development and under pathological condition; 2) gain new insight into the mechanisms underlying the pathogenesis of respiratory disorders inherent in the diseases involving cigarette smoking (PNE) and hypoxemia, such as SIDS; and 3) help us to develop new preventive strategies and pharmacological therapies for these patients.

描述（由申请人提供）：婴儿猝死综合症（SIDS）是婴儿死亡的主要原因。香烟烟雾（尼古丁暴露）是关键的危险因素，而低氧血症是 SIDS 的急性前兆。尽管对 SIDS 的致病机制知之甚少，但低氧通气反应 (dHVR) 抑制被认为是主要因素。现有的由传统产前烟碱暴露 (tPNE) 诱导的 SIDS 动物模型显示，幼鼠在 60 分钟严重缺氧期间死亡率过高 (15%)。该项目的目标 1 是通过使用更现实的“足月”PNE (fPNE) 来改进该模型，该模型包括怀孕前、怀孕期间和哺乳期，以最大限度地提高 PNE 对心肺功能的不利影响。此外，dHVR 在死亡率中的因果作用以及 dHVR 的中心起源将得到进一步明确。最近，我们发现支气管肺 C 激发器 (PCF) 失活独特地消除了在肺部炎症大鼠中观察到的 dHVR，这表明 PCF 在病理条件下削弱 HVR 方面发挥着关键作用。据报道，PCF 对香烟烟雾（尼古丁）敏感，并主要通过作用于 A1 受体（A1R）而受到缺氧产物腺苷（AD）的刺激。这些发现，加上 SIDS 受害者迷走神经 C 纤维的增加，导致了目标 2，其中我们将确定 fPNE 诱导的 dHVR 和死亡是否依赖于 AD 刺激 PCF，以及 fPNE 是否主要通过以下方式放大 PCF 对缺氧 (AD) 的反应：在我们的模型中增加 PCF 的数量和 A1R。人们普遍认为，PCF 的激活通过释放谷氨酸来抑制通气，谷氨酸通过作用于 AMPA 受体 (AMPAR) 刺激尾侧和中孤束核 (mNTS) 中 PCF 驱动的神经元。这种抑制作用通过作用于神经激肽 1 受体 (NK1R) 的局部 P 物质 (SP) 得到放大。最重要的是，局部 SP 释放是由颈动脉体的缺氧刺激介导的，并且在 SIDS 患者中大大增加。因为在我们的试验数据中，fPNE 上调 mNTS NK1R 表达，目标 3 中的研究将确定 fPNE 是否促进 NK1R 和 SP 合成以及 mNTS 中缺氧诱导的 SP 释放，以通过 SP 促进 AMPAR 介导的神经元活动来集中增强 PCF 驱动的神经元活动，导致 dHVR。拟议的研究将通过电生理学、药理学、免疫细胞化学和分子方法在大鼠幼崽中进行。我们在目标中描述的预测结果将：1）产生 PCF 可塑性和 PCF 在出生后发育和病理条件下控制呼吸中的作用的新概念； 2) 对涉及吸烟（PNE）和低氧血症的疾病（例如 SIDS）固有的呼吸系统疾病的发病机制获得新的认识； 3）帮助我们为这些患者开发新的预防策略和药物疗法。