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: 8646986
• 负责人: Fadi Xu
• 金额: $ 42.34万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646986
• 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. PUBLIC HEALTH RELEVANCE: We will establish the key role a depressed ventilatory response to hypoxia (dHVR) plays in the mortality observed in a new SIDS animal model and further elucidate the peripheral and central mechanisms underlying this dVHR. These studies will broaden our knowledge of respiratory pathophysiology, yield a new concept of SIDS genesis and, most importantly, may highlight new targets for preventing and therapeutically intervening in the respiratory failure in SIDS victims.

描述（由申请人提供）：婴儿猝死综合征（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，低氧血症是小岛屿发展中国家的急性前兆。虽然小岛屿发展中国家的致病机制尚不清楚，但低氧通气反应（dHVR）被认为是一个主要因素。传统的产前尼古丁暴露（tPNE）诱导的SIDS动物模型显示，大鼠幼崽在60分钟严重缺氧期间死亡率过高（15%）。该项目的目的1是通过使用更现实的“足月”PNE （fPNE）来改进该模型，fPNE包括怀孕前和怀孕和哺乳期间，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和dHVR的中心起源将进一步确定。最近，我们发现支气管肺c -火（PCFs）的失活可以独特地消除肺部炎症大鼠的dHVR，这表明PCFs在病理状态下对HVR的钝化起着关键作用。据报道，pcf主要通过作用于A1受体（A1R）而被香烟烟雾（尼古丁）致敏，并被缺氧产物腺苷（AD）刺激。这些发现，以及SIDS患者迷走神经c -纤维的增加，导致Aim 2，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是否主要通过增加模型中PCF的数量和A1Rs来增强PCF对缺氧（AD）的反应。一般认为，pcf的激活通过释放谷氨酸抑制通气，谷氨酸通过作用于AMPA受体（AMPAR）刺激孤束核尾核和中核的pcf驱动神经元。这种抑制作用被局部P物质（SP）作用于神经激肽1受体（NK1R）而放大。最重要的是，局部SP释放是通过对颈动脉体的缺氧刺激介导的，并且在SIDS患者中大大升高。由于在我们的先导数据中，fPNE上调了mNTS NK1R的表达，Aim 3的研究将确定fPNE是否促进NK1R和SP的合成以及缺氧诱导的mNTS中SP的释放，从而通过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，从而导致dHVR。本研究将采用电生理、药理学、免疫细胞化学和分子方法在大鼠幼鼠中进行。我们在目标中描述的预测结果将：1)产生PCFs的可塑性和PCFs在出生后发育和病理状态下控制呼吸的作用的新概念；2)对吸烟和低氧血症疾病（如小岛屿发展中国家）所固有的呼吸系统疾病的发病机制有了新的认识；3)帮助我们为这些患者开发新的预防策略和药物治疗。