Cytokines and Neonatal Respiratory Control

描述（由申请人提供）：在早期发育期间暴露于促炎细胞因子似乎在启动新生儿肺和脑损伤中起关键作用。不幸的是，在这些部位连接细胞因子介导的病理生理的途径和机制尚不清楚。本提案的目标是创建一个新的发育模型，以表征肺部发起的炎症反应触发大脑相应反应的能力，并开始利用新生儿呼吸控制作为肺/脑相互作用的生理测量。具体来说，我们试图验证一种假设，即内毒素诱导的未成熟肺炎症反应会触发脑干呼吸相关区域的细胞因子产生，从而导致呼吸控制受损。在我们的初步研究中，我们证明暴露于气管内脂多糖（LPS）的大鼠幼鼠与生理盐水对照相比，脑干中的IL- 1b和IL-6 mRNA增加，迷走神经切除术降低了IL- 1b mRNA对LPS暴露的脑干反应。我们还证实了IL-1b受体在脑干呼吸相关区域的存在，包括孤束核，它是迷走神经传入的一级中枢突触。最后，我们记录了LPS与生理盐水暴露大鼠幼崽对缺氧的通气反应减弱。在目前的提议中，我们试图描述：迷走神经传入在脑干细胞因子表达的调节中的作用，以响应肺内LPS（目的1），细胞因子信息的解剖位置，脑干中蛋白质和受体的表达（目的2），以及与LPS诱导的肺部炎症相关的呼吸控制的改变（目的3）。所有的生化、解剖、分子和生理学研究将在10-12日龄的大鼠幼崽中进行。这些建议的研究将作为未来实验的框架，以探索由外周炎症刺激启动的脑干细胞因子产生在调节新生儿呼吸控制的神经递质通路中的作用。

DESCRIPTION (provided by applicant): Exposure to proinflammatory cytokines during early development appears to play a key role in initiating both neonatal lung and brain injury. Unfortunately, the pathways and mechanisms that link cytokine-mediated pathophysiology at these sites are not known. The goal of this proposal is to create a new developmental model to characterize the ability of an inflammatory response initiated in the lung to trigger a corresponding response in the brain and begin to utilize neonatal respiratory control as a physiologic measure of this lung/brain interaction. Specifically, we seek to test the hypothesis that an endotoxin induced inflammatory response in the immature lung triggers cytokine production in respiratory-related areas of the brainstem and resultant impairment of respiratory control. In our preliminary studies we demonstrated that rat pups exposed to intratracheal lipopolysaccharide (LPS) versus saline controls exhibited increased IL- 1b and IL-6 mRNA in the brainstem and that vagotomy decreased this brainstem response of IL- 1b mRNA to LPS exposure. We have additionally demonstrated the presence of IL-1b receptors in respiratory-related areas of the brainstem including the nucleus tractus solitarius, which serves as the first order central synapse for vagal afferents. Finally, we have documented a diminished ventilatory response to hypoxia in LPS versus saline exposed rat pups. In the current proposal we seek to characterize: the role of vagal afferents in modulation of brainstem cytokine expression in response to intrapulmonary LPS (Aim 1), the anatomical sites of cytokine message, protein and receptor expression in the brainstem (Aim 2) and the alteration of respiratory control associated with LPS-induced lung inflammation (Aim 3). All biochemical, anatomical, molecular and physiological studies will be performed in 10-12 day-old rat pups. The proposed studies will serve as the framework for future experiments to explore the role of brainstem cytokine production initiated by a peripheral inflammatory stimulus in modulating neurotransmitter pathways that regulate neonatal respiratory control. PUBLIC HEALTH RELEVANCE: Inflammatory processes are a major cause of morbidity for both the developing brain and lung of preterm and term infants. In this proposal we seek to address the mechanism whereby lung inflammation in early life elicits an inflammatory response in the immature brain and resultant impairment of respiratory control.