Cytokines and Neonatal Respiratory Control

细胞因子和新生儿呼吸控制

基本信息

批准号：
8092652
负责人：
RICHARD JOHN MARTIN
金额：
$ 19.63万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8092652
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 Functional disorder Future Goals Hour Hypoxia Impairment In Situ Hybridization Infant Infection Infection of amniotic sac and membranes Inflammation Inflammatory Inflammatory Response Interleukin-1 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 lung injury neonatal sepsis paraform premature protein expression public health relevance pup receptor receptor expression relating to nervous system research study respiratory response

项目摘要

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（由申请人提供）：早期发育过程中促炎性细胞因子的暴露似乎在发起新生儿肺和脑损伤方面起着关键作用。不幸的是，在这些部位连接细胞因子介导的病理生理学的途径和机制尚不清楚。该提案的目的是创建一个新的发展模型，以表征肺部在肺部触发相应反应的炎症反应的能力，并开始利用新生儿呼吸道控制作为这种肺/脑相互作用的生理度量。具体而言，我们试图检验以下假设：内毒素在脑干的呼吸相关区域中诱导的未成熟肺部炎症反应触发细胞因子的产生并导致呼吸控制损害。在我们的初步研究中，我们证明了暴露于气管内脂多糖（LPS）与盐水对照的大鼠幼崽在脑干中表现出IL-1B和IL-6 mRNA的增加，并且迷走术降低了IL-1B mRNA对LPS暴露的脑干反应。我们还证明了在脑干的呼吸相关区域中存在IL-1B受体，包括巨核solitarius，它是迷走神经传入的一阶中央突触。最后，我们记录了对LPS与盐水暴露的大鼠幼犬缺氧的通气反应减少。在当前的建议中，我们试图表征：迷走神经传入在响应肺内LPS的脑干细胞因子表达中的作用（AIM 1），细胞因子信息的解剖部位，蛋白质和受体在脑干中的表达（AIM 2）以及与LPS诱导的肺部炎症相关的呼吸道控制的改变（AIM 2）。所有生化，解剖学，分子和生理研究都将在10-12天大的大鼠幼崽中进行。拟议的研究将作为未来实验的框架，以探索由周围炎症刺激在调节调节新生儿呼吸控制的神经递质途径中引发的脑干细胞因子产生的作用。公共卫生相关性：炎症过程是对早产和年龄婴儿发展的大脑和肺部发病率的主要原因。在这项建议中，我们试图解决早期肺部炎症引起未成熟大脑的炎症反应并导致呼吸控制损害的机制。