The Upper Airway and the Sudden Infant Death Syndrome

描述（由申请人提供）：由于开展了有利于婴儿仰卧姿势睡眠的教育活动，美国和其他地方的婴儿猝死综合征（SIDS）的发病率已大幅下降。尽管取得了这一成功，小岛屿发展中国家仍然是婴儿死亡率的主要原因。要在预防SIDS方面取得进一步进展，可能需要更好地了解其发病机制。喉化学反射（LCR）-呼吸暂停和吞咽反应喉内的水，牛奶或其他液体-是更突出的新生动物和人类婴儿比成人，因此，长期以来一直被怀疑为一个原因，一些情况下的SIDS。在过去的四年中，我们发现在新生仔猪中，LCR被大大夸大，这些仔猪的体温比正常体温高出1- 3摄氏度。这种体温过高的效果是可逆的，通过身体冷却，可以在同一动物身上重复多次。喉水感受器不受温度变化的影响，在这个范围内，但局部变暖的延髓的孤束核（NTS）的区域，从喉传入使其与控制呼吸和吞咽的神经元的突触连接，可逆地夸大LCR，强烈暗示了一个延髓的作用部位，以前证明的全身变暖的影响LCR。延髓温度对LCR持续时间和强度的影响是一个引人注目的新发现，这在SIDS的发病机制中具有非常重要的意义。在这次更新申请中，我们将研究这种温度效应的机制，并将其置于与小岛屿发展中国家有关的其他研究结果的背景下。我们将研究去脑小猪以确定（1）通过高温引起的喉部呼吸暂停的加重是否是由于中枢神经系统的主要抑制性神经递质GABA的过度活性，（2）喉部呼吸暂停的热加重是否受到在髓质中的神经递质的操纵的影响，所述神经递质的受体已被证明在SIDS婴儿中缺乏，（3）在正常和升高的体温下，NTS中温度敏感神经元在喉呼吸暂停诱发过程中的行为;（4）TRPV 1通道是否参与喉呼吸暂停的热加重。我们还将研究完整的，长期仪器在清醒，NREM和REM睡眠期间的小猪，以确定在更自然的条件下，高温和中枢神经系统神经递质的操纵对LCR的综合影响。这些实验的结果将提供有关温度和神经递质对LCR的相互作用的见解，并可能导致对SIDS高风险群体中的婴儿进行合理的预防性治疗。7.公共卫生相关性：婴儿猝死综合症（SIDS）--一个表面上健康的婴儿通常在睡眠中意外死亡--是婴儿死亡的主要原因，也是婴儿父母的灾难性事件。SIDS的一个可疑机制是胃内容物进入喉部，引发强烈的反射，停止呼吸，导致缺氧死亡。我们将研究这种反射及其在新生仔猪体温升高时的增强，以努力找到SIDS易感性的检测方法和被确定为有风险的婴儿的预防性治疗方法。

DESCRIPTION (provided by applicant): The incidence of the Sudden Infant Death Syndrome (SIDS) has decreased substantially in the United States and elsewhere as a result of educational campaigns favoring the supine posture for sleeping infants. Despite this success, SIDS remains a major contributor to infant mortality. Further progress in the prevention of SIDS is likely to require improved understanding of its pathogenesis. The laryngeal chemoreflex (LCR)-apnea and swallowing in response to intralaryngeal water, milk or other fluids-is more prominent in newborn animals and human infants than in adults and, therefore, has long been suspected as a cause of some cases of SIDS. We found during the past four years that the LCR is greatly exaggerated in neonatal piglets that are warmed 1- 3 0C above their normal body temperatures. This effect of hyperthermia is reversible by body cooling and can be repeated several times in the same animal. The laryngeal water receptors are not influenced by temperature changes in this range, but locally warming the medulla in the region of the nucleus of the solitary tract (NTS), where afferents from the larynx make their synaptic connections with neurons that control breathing and swallowing, reversibly exaggerates the LCR, strongly implying a medullary site of action for the previously demonstrated effect of whole body warming on the LCR. The influence of medullary temperature on the duration and intensity of the LCR is a striking new finding, which is of compelling importance in the pathogenesis of SIDS. In this renewal application, we will study the mechanism of this temperature effect and place it in the context of other findings related to SIDS. We will study decerebrate piglets to determine (1) whether the exaggeration of laryngeal apnea by hyperthermia is due to excessive activity of GABA, the major inhibitory neurotransmitter of the central nervous system, (2) whether the thermal exaggeration of laryngeal apnea is influenced by manipulation in the medulla of neurotransmitters whose receptors have been shown to be deficient in SIDS infants, (3) the behavior of temperature sensitive neurons in the NTS during elicitation of laryngeal apnea at normal and elevated body temperatures and (4) whether TRPV1 channels are involved in the thermal exaggeration of laryngeal apnea.. We will also study intact, chronically instrumented piglets during wakefulness, NREM and REM sleep to determine the combined influence on the LCR of hyperthermia and manipulation of central nervous system neurotransmitters under more natural conditions. The results of these experiments will provide insight about the interactions of temperature and neurotransmitters on the LCR and may lead to rational preventive therapies for infants in groups that are at high risk for SIDS. 7. PUBLIC HEALTH RELEVANCE: Sudden Infant Death Syndrome (SIDS) - the unexpected death of an apparently healthy baby, usually during sleep - is a major cause of infant mortality and a devastating event for the baby's parents. One suspected mechanism of SIDS is that stomach contents, regurgitated into the larynx, trigger a powerful reflex that stops breathing and leads to death from oxygen lack. We will examine this reflex and its enhancement by increased body temperature in neonatal piglets in an effort to find tests for SIDS susceptibility and preventive treatments for infants identified as being at risk.