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:
- 金额:$ 19.63万
- 依托单位:
- 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:
- 关键词:AddressAfferent PathwaysAllergensApneaAreaAstrocytesBilateralBiochemicalBrainBrain InjuriesBrain StemCarotid BodyCellsCervicalCharacteristicsClinicalDataDevelopmentEndotoxinsEnzyme-Linked Immunosorbent AssayExhibitsExposure toFunctional disorderFutureGoalsHourHypoxiaImpairmentIn Situ HybridizationInfantInfectionInfection of amniotic sac and membranesInflammationInflammatoryInflammatory ResponseInterleukin-1Interleukin-1 betaInterleukin-6LifeLinkLipopolysaccharidesLungLung InflammationMeasuresMediatingMessenger RNAMicrogliaModelingMolecularMorbidity - disease rateNeonatalNerveNeurogliaNeuronsNeurotransmittersNucleus solitariusOrganismPathway interactionsPerinatalPeripheralPhysiologicalPlayPremature BirthProcessProductionProteinsRattusRespiratory CenterRespiratory SystemReverse Transcriptase Polymerase Chain ReactionRoleSalineSiteSliceStagingStimulusSynapsesTestingTimeUp-RegulationVagotomycarotid sinuscell typecytokineinnovationinsightneonatal lung injuryneonatal sepsisparaformprematureprotein expressionpublic health relevancepupreceptorreceptor expressionrelating to nervous systemresearch studyrespiratoryresponse
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):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方面发挥了关键作用。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。这项建议的目标是创建一种新的发育模型,以表征在肺部启动的炎症反应在大脑中触发相应反应的能力,并开始利用新生儿呼吸控制作为这种肺/脑相互作用的生理指标。具体地说,我们试图测试这样一种假设,即内毒素在未成熟的肺中诱导炎症反应,触发脑干呼吸相关区域的细胞因子产生,从而损害呼吸控制。在我们的初步研究中,我们证明,与生理盐水对照组相比,气管内注射脂多糖(LPS)的大鼠脑干中IL-1b和IL-6mRNA的表达增加,迷走神经切断术降低了IL-1b mRNA对LPS暴露的脑干反应。此外,我们还证明了IL-1b受体存在于脑干的呼吸相关区域,包括孤束核,它是迷走神经传入的第一级中央突触。最后,我们记录了与生理盐水暴露的大鼠相比,脂多糖对低氧的呼吸反应减弱。在目前的方案中,我们试图描述:迷走神经传入在肺内毒素刺激下调节脑干细胞因子表达中的作用(目标1),脑干细胞因子信息、蛋白质和受体表达的解剖位置(目标2)以及与内毒素诱导的肺部炎症相关的呼吸控制的改变(目标3)。所有的生化、解剖学、分子和生理学研究将在10-12日龄的大鼠幼鼠身上进行。这些拟议的研究将作为未来实验的框架,以探索外周炎性刺激启动的脑干细胞因子产生在调节神经递质途径中的作用,这些神经递质通路调节新生儿呼吸控制。
公共卫生相关性:炎症过程是早产儿和足月儿发育中的脑和肺发病率的主要原因。在这项建议中,我们试图解决早期肺部炎症在未成熟的大脑中引起炎症反应并由此导致呼吸控制障碍的机制。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Changes in carotid body and nTS neuronal excitability following neonatal sustained and chronic intermittent hypoxia exposure.
- DOI:10.1016/j.resp.2014.09.015
- 发表时间:2015-01-01
- 期刊:
- 影响因子:2.3
- 作者:Mayer CA;Wilson CG;MacFarlane PM
- 通讯作者:MacFarlane PM
Intrapulmonary lipopolysaccharide exposure upregulates cytokine expression in the neonatal brainstem.
- DOI:10.1111/j.1651-2227.2011.02564.x
- 发表时间:2012-05
- 期刊:
- 影响因子:0
- 作者:Balan KV;Kc P;Mayer CA;Wilson CG;Belkadi A;Martin RJ
- 通讯作者:Martin RJ
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RICHARD JOHN MARTIN其他文献
RICHARD JOHN MARTIN的其他文献
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{{ truncateString('RICHARD JOHN MARTIN', 18)}}的其他基金
Patterns of Hypoxia and Mortality in the SUPPORT Trial Cohort
支持试验队列中的缺氧和死亡率模式
- 批准号:
8759060 - 财政年份:2014
- 资助金额:
$ 19.63万 - 项目类别:
LOW DOSE INHALED NITRIC OXIDE TO PREVENT CHRONIC LUNG DISEASE IN PRETERM INFANTS
低剂量吸入一氧化氮预防早产儿慢性肺病
- 批准号:
7378042 - 财政年份:2006
- 资助金额:
$ 19.63万 - 项目类别:
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