Cytokines and Neonatal Respiratory Control

细胞因子和新生儿呼吸控制

• 批准号: 7982041
• 负责人: RICHARD JOHN MARTIN
• 金额: $ 23.55万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7982041
• 关键词: Address; Afferent Pathways; Allergens; Apnea; Area; Astrocytes; Bilateral; Biochemical; Brain; Brain Injuries; Brain Stem; Carotid Body; Cells; Cervical; Characteristics; Clinical; Data; Development; Endotoxins; Enzyme-Linked Immunosorbent Assay; Exhibits; Exposure to; Figs - dietary; Functional disorder; Future; Goals; Hour; Hypoxia; Impairment; In Situ Hybridization; Infant; Infection; Infection of amniotic sac and membranes; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-6; Life; Link; Lipopolysaccharides; Lung; Lung Inflammation; Measures; Mediating; Messenger RNA; Microglia; Modeling; Molecular; Morbidity - disease rate; Neonatal; Nerve; Neuroglia; Neurons; Neurotransmitters; Nucleus solitarius; Organism; Pathway interactions; Perinatal; Peripheral; Physiological; Play; Premature Birth; Process; Production; Proteins; Rattus; Respiratory Center; Respiratory System; Reverse Transcriptase Polymerase Chain Reaction; Role; Saline; Site; Slice; Staging; Stimulus; Synapses; Testing; Time; Up-Regulation; Vagotomy; carotid sinus; cell type; cytokine; innovation; insight; neonatal sepsis; paraform; premature; public health relevance; pup; receptor; receptor expression; relating to nervous system; research study; respiratory; response

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.

描述（由申请方提供）：在早期发育期间暴露于促炎细胞因子似乎在引发新生儿肺和脑损伤中起关键作用。不幸的是，在这些网站上的连接甘氨酸介导的病理生理学的途径和机制是未知的。本提案的目标是创建一个新的发育模型，以表征肺中启动的炎症反应触发脑中相应反应的能力，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，我们试图测试的假设，内毒素诱导的炎症反应在未成熟的肺触发细胞因子的生产在脑干和呼吸控制的损害相关领域。在我们的初步研究中，我们表明，暴露于内毒素脂多糖（LPS）与盐水对照组的大鼠幼崽表现出增加的IL- 1b和IL-6的mRNA在脑干和迷走神经切断术降低这种脑干反应的IL- 1b mRNA的LPS暴露。我们还证明了IL-1b受体的存在下，包括孤束核，作为迷走神经传入神经的一级中枢突触的脑干的兴奋相关领域。最后，我们已经证明了LPS与盐水暴露的大鼠幼崽对缺氧的反应减弱。在目前的建议中，我们试图表征：迷走神经传入在调节脑干细胞因子表达中的作用，以响应肺内LPS（目的1），脑干中细胞因子信息，蛋白质和受体表达的解剖部位（目的2）和与LPS诱导的肺部炎症相关的呼吸控制的改变（目的3）。所有生物化学、解剖学、分子和生理学研究将在10-12日龄大鼠幼仔中进行。拟议的研究将作为未来实验的框架，以探讨脑干细胞因子的产生所引发的外周炎症刺激在调节神经递质通路，调节新生儿呼吸控制的作用。 公共卫生相关性：炎症过程是早产儿和足月儿脑和肺发育中发病的主要原因。在这个建议中，我们试图解决的机制，即肺部炎症在生命早期elevates一个炎症反应，在未成熟的大脑和呼吸控制的损害。