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

基本信息

批准号：
8085046
负责人：
Fadi Xu
金额：
$ 43.2万
依托单位：
LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
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/8085046
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 pup receptor receptor expression respiratory response

项目摘要

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）：猝死综合征（SIDS）是婴儿死亡率的主要原因。香烟烟雾（烟碱暴露）是关键危险因素，低氧血症是SIDS的急性前体。尽管SIDS的致病机制知之甚少，但假定抑郁症的缺氧通气反应（DHVR）是主要参与者。由传统产前烟碱暴露（TPNE）引起的现有SIDS动物模型在大鼠幼犬的60分钟严重缺氧中表现出过多的死亡率（15％）。该项目的目标1是通过使用更现实的“完整” PNE（FPNE）来改善该模型的目标，该PNE（FPNE）由怀孕前和怀孕期间和泌乳期间的时期组成，以最大程度地对心脏呼吸功能产生不利影响。此外，将进一步定义DHVR在死亡率和DHVR的中心起源中的因果作用。最近，我们发现，支气管肺C对方（PCF）灭活，独特地消除了在患有肺部炎症的大鼠中观察到的DHVR，这表明PCF在病理状态下HVR的关键作用至关重要。据报道，PCF通过香烟烟雾（尼古丁）敏感，并由低氧产物腺苷（AD）刺激，主要是通过作用于A1受体（A1R）。这些发现，以及在SIDS受害者中增加的迷走神经C纤维，导致AIM 2，我们将确定FPNE诱导的DHVR和死亡是否取决于AD刺激PCF的AD以及FPNE是否通过在我们的模型中增加PCF的人群和A1RS来扩大PCF对低氧（AD）的反应。人们普遍认为，PCF的激活通过释放谷氨酸抑制通风，从而刺激尾部和中部核中核和中部核丝菌（MNT）中PCF驱动的神经元（MNT）通过作用于AMPA受体（AMPAR）。作用于神经蛋白1受体（NK1R）的局部物质P（SP）扩大了这种抑制作用。最重要的是，局部SP的释放是通过颈动脉体的低氧刺激介导的，在小岛屿发展中国家受害者中升高。由于FPNE在我们的试点数据中上调了MNTS NK1R的表达，因此AIM 3中的研究将定义FPNE是否促进NK1R和SP合成以及MNTS中缺氧诱导的SP释放，以中央增强PCF PCF驱动的神经元活动，从而通过SP促进AMPAR-AMPAR介导的神经元活动，从而导致DHVR。拟议的研究将通过使用电生理，药理，免疫细胞化学和分子方法在大鼠幼崽中进行。我们的预测结果如目的所述：1）在产后发育期间和病理状况下，在控制呼吸中的PCFS“可塑性和PCF”作用中产生了新的概念； 2）对涉及香烟吸烟（PNE）和低氧血症（例如SIDS）固有的呼吸系统疾病发病机理的机制有了新的了解； 3）帮助我们为这些患者制定新的预防策略和药理疗法。公共卫生相关性：我们将确定对缺氧（DHVR）在新的SIDS动物模型中观察到的死亡率中的抑郁通气反应（DHVR）的关键作用，并进一步阐明了该DVHR的外围和中心机制。这些研究将扩大我们对呼吸道病理生理学的了解，产生新的SIDS创世纪的概念，最重要的是，可能会突出预防和治疗介绍SIDS受害者呼吸衰竭的新目标。