The Upper Airway and the Sudden Infant Death Syndrome

描述(申请人提供)：由于支持婴儿睡姿的教育活动，在美国和其他地方，婴儿猝死综合症(SID)的发病率大幅下降。尽管取得了这一成功，但小岛屿发展中国家仍然是婴儿死亡率的主要贡献者。在预防小岛屿发展中国家方面的进一步进展可能需要更好地了解其发病机制。喉部化学反射(LCR)--对咽内水、牛奶或其他液体产生呼吸暂停和吞咽反应--在新生动物和人类婴儿中比成人更突出，因此长期以来一直被怀疑是一些SID病例的原因。我们在过去的四年中发现，在比正常体温高出1-3.0摄氏度的新生仔猪身上，LCR被大大夸大了。这种体温过高的效应通过身体降温是可逆的，并且可以在同一动物身上重复几次。在这个范围内，喉水受体不受温度变化的影响，但局部加热孤束核(NTS)区域的延髓，来自喉部的传入信号与控制呼吸和吞咽的神经元建立突触联系，可逆地夸大LCR，强烈暗示先前证明的全身升温对LCR的影响是延髓的作用部位。脊髓温度对LCR持续时间和强度的影响是一个引人注目的新发现，在SIDS的发病机制中具有重要意义。在这次更新申请中，我们将研究这种温度效应的机制，并将其放在与小岛屿发展中国家相关的其他发现的背景下。我们将对去脑仔猪进行研究，以确定(1)高温是否由于中枢神经系统主要抑制性神经递质GABA的过度活动而导致喉呼吸暂停的过度夸大，(2)神经递质的髓质中的操作是否影响喉呼吸暂停的热夸大，而神经递质的受体在SIDS婴儿中已被证明是缺陷的；(3)正常体温和体温升高时，NTS中对温度敏感的神经元的行为；(4)TRPV1通道是否参与了喉呼吸暂停的热夸大。我们还将研究清醒、NREM和REM睡眠中完整的、长期使用仪器的小猪，以确定在更自然的条件下高温和操纵中枢神经系统神经递质对LCR的联合影响。这些实验的结果将深入了解温度和神经递质在LCR上的相互作用，并可能导致对SID高危人群中的婴儿进行合理的预防治疗。7.与公共卫生有关：婴儿猝死综合症是婴儿死亡的一个主要原因，对婴儿的父母来说是一件毁灭性的事件。小儿麻痹症的一个可疑机制是，胃内容物反流到喉部，引发强烈的反射，停止呼吸，导致缺氧死亡。我们将检查这种反射及其通过新生仔猪体温升高而增强的情况，以努力找到SID易感性的测试和对被确定为处于危险中的婴儿的预防性治疗。

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.