The Upper Airway and the Sudden Infant Death Syndrome

描述（由申请人提供）：在美国和其他地方，由于提倡婴儿仰卧姿势的教育活动，婴儿猝死综合症（SIDS）的发病率已经大幅下降。尽管取得了这样的成功，小岛屿发展中国家仍然是造成婴儿死亡率的一个主要因素。要在预防小岛屿发展中国家方面取得进一步进展，可能需要进一步了解其发病机制。喉化学反射（LCR）——对咽内水、奶或其他液体作出反应时的呼吸暂停和吞咽——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一些SIDS病例的原因。在过去的四年中，我们发现，在高于正常体温1- 30℃的新生仔猪中，LCR被大大夸大。体温过高的这种影响可以通过身体降温来逆转，并且可以在同一动物身上重复几次。在这个范围内，喉部水受体不受温度变化的影响，但局部加热孤立束核（NTS）区域的髓质，喉的传入与控制呼吸和吞咽的神经元建立突触连接，可逆地夸大了LCR，强烈暗示了先前证明的全身加热对LCR的影响的作用部位是髓质。髓质温度对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的发病机制中具有引人注目的重要性。在这项更新申请中，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。我们将对失觉仔猪进行研究，以确定(1)热疗引起的喉呼吸暂停的延长是否由于中枢神经系统的主要抑制性神经递质GABA的过度活性所致；(2)喉呼吸暂停的热延长是否受到神经递质的调节的影响，这些神经递质受体在SIDS婴儿中已被证明是缺乏的。(3)正常体温和升高体温下NTS温度敏感神经元在喉呼吸暂停引发过程中的行为；(4)TRPV1通道是否参与喉呼吸暂停的热放大。我们还将在清醒、非快速眼动和快速眼动睡眠期间对完整的、长期使用仪器的仔猪进行研究，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作对LCR的综合影响。这些实验的结果将提供关于温度和神经递质在LCR上的相互作用的见解，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）——表面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，对婴儿的父母来说是一个毁灭性的事件。小岛屿发展中国家的一个被怀疑的机制是，胃内容物反刍到喉部，引发强烈的反射，停止呼吸，导致缺氧死亡。我们将在新生仔猪中研究这种反射及其通过体温升高而增强的情况，努力找到SIDS易感性的测试方法，并对确定有危险的婴儿进行预防性治疗。

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.