The Upper Airway and the Sudden Infant Death Syndrome

描述（由申请人提供）：由于提倡婴儿仰卧姿势的教育活动，婴儿猝死综合症（SIDS）的发病率在美国和其他地方已大幅下降。尽管取得了这一成功，SIDS 仍然是婴儿死亡率的一个主要因素。预防 SIDS 的进一步进展可能需要加深对其发病机制的了解。喉化学反射（LCR）——对喉内水、牛奶或其他液体的反应而导致的呼吸暂停和吞咽——在新生动物和人类婴儿中比在成人中更为突出，因此长期以来一直被怀疑是某些 SIDS 病例的原因。我们在过去四年中发现，新生仔猪的 LCR 在比正常体温高 1-3 0C 的情况下被大大夸大。这种高热效应可以通过身体冷却而逆转，并且可以在同一只动物身上重复多次。喉部水感受器不受此范围内温度变化的影响，但会局部加热孤束核（NTS）区域的延髓，来自喉部的传入神经与控制呼吸和吞咽的神经元建立突触连接，可逆地夸大LCR，强烈暗​​示先前证明的全身变暖对LCR影响的延髓作用部位。髓质温度对 LCR 持续时间和强度的影响是一项引人注目的新发现，这在 SIDS 的发病机制中具有极其重要的意义。在此更新应用中，我们将研究这种温度效应的机制，并将其置于与 SIDS 相关的其他研究结果的背景下。我们将研究去大脑仔猪，以确定（1）高温引起的喉部呼吸暂停是否是由于中枢神经系统主要抑制性神经递质 GABA 的过度活动所致，（2）喉部呼吸暂停的热加剧是否受到神经递质髓质操作的影响，这些神经递质的受体已被证明在 SIDS 婴儿中存在缺陷，（3）在正常和升高的体温下引起喉部呼吸暂停期间的NTS，以及（4）TRPV1通道是否参与了喉部呼吸暂停的热过度。我们还将研究在清醒、NREM和REM睡眠期间完整的、长期使用仪器的仔猪，以确定在更自然的条件下热疗和中枢神经系统神经递质的操纵对LCR的综合影响。这些实验的结果将深入了解温度和神经递质对 LCR 的相互作用，并可能为 SIDS 高风险群体的婴儿提供合理的预防性治疗。 7. 公共卫生相关性：婴儿猝死综合症（SIDS）——看似健康的婴儿通常在睡眠期间意外死亡——是婴儿死亡的主要原因，对婴儿的父母来说也是毁灭性的事件。 SIDS 的一个可疑机制是胃内容物反流到喉部，引发强烈的反射，导致呼吸停止并导致缺氧死亡。我们将检查新生仔猪的这种反射及其因体温升高而增强的情况，以期找到针对 SIDS 易感性的测试方法，并为确定有风险的婴儿找到预防性治疗方法。

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.