Mechanisms of Fetal Inflammatory Response Syndrome Induced by Chorioamnionitis

描述（由申请人提供）：绒毛膜羊膜炎或胎膜炎症存在于约70%的妊娠30周前出生的早产儿中，是这一人群发病率和死亡率的主要因素。胎儿炎症反应综合征（FIRS）存在于约50%暴露于绒毛膜羊膜炎的早产儿中，并被认为是绒毛膜羊膜炎诱导胎儿损伤反应的中介。尽管许多流行病学研究表明FIRS是早产新生儿不良神经、胃肠道和肺部结局的一个强大危险因素，但对FIRS的机制或发病机制知之甚少。在了解FIRS是如何启动或发出信号的过程中，一个主要的障碍是缺乏适当的动物模型。这一建议将验证胎儿暴露于绒毛膜羊膜炎诱导全身炎症反应的假设，这种炎症反应是由羊膜间室中的IL-1信号引发的，并由全身先天免疫反应调节。本实验将采用本课组研制的羊膜内毒素致羊膜炎早产儿羊模型，该模型与人类病理非常接近。这一应用是基于我们的初步数据，IL-1信号是介导羊膜内毒素诱导的肺部炎症反应所必需的，绵羊胎儿适应羊膜内毒素的反复暴露，单核细胞对内毒素的反应降低。在具体目标1中，我们将定义绒毛膜、肺和胃肠道对内毒素诱导的FIRS发展的相对贡献。我们将利用我们小组开发的胎儿外科方法来分离每个器官。在特异性目标2中，我们将测试羊膜内IL-1是否会导致FIRS，并使用IL-1受体拮抗剂确定LPS诱导的FIRS中IL-1信号的需求。在特异性目标3中，我们将评估胎儿对反复暴露于羊膜内毒素的适应和内毒素耐受性。我们的长期目标是了解暴露于绒毛膜羊膜炎后全身性炎症和器官损伤反应的机制。这项拨款将提供一个框架，在整个动物水平上理解FIRS问题。这项工作将为开发治疗策略提供必要的见解，如选择性羊膜内抗炎治疗，以改善暴露于绒毛膜羊膜炎的早产儿的预后。公共卫生相关性：绒毛膜羊膜炎和相关的全身炎症反应在早产儿中引起显著的发病率，是该人群的一个主要公共卫生问题。这项拨款将确定羊膜内毒素引起羊膜羊膜炎羊模型的全身炎症反应机制。这一知识对于制定旨在改善早产儿结局的治疗方法至关重要。

DESCRIPTION (provided by applicant): Chorioamnionitis or inflammation in the fetal membranes is present in about 70% of the preterm infants born before 30 weeks gestation and is a major contributor to the morbidity and mortality in this population. Fetal inflammatory response syndrome (FIRS) is present in about 50% of preterm infants exposed to chorioamnionitis and thought to be the mediator of chorioamnionitis induced fetal injury responses. Despite many epidemiological studies implicating FIRS as a strong risk factor for adverse neurological, gastrointestinal and pulmonary outcomes in preterm neonates, very little is known about the mechanism or the pathogenesis of FIRS. A major stumbling block in the progress of understanding how FIRS is initiated or signaled is the lack of appropriate animal models. This proposal will test the hypothesis that fetal exposure to chorioamniontis induces a systemic inflammatory response that is initiated by IL-1 signaling in the amniotic compartment and is modulated by systemic innate immune responses. The experiments will utilize the preterm fetal sheep model of chorioamniontis induced by intraamniotic endotoxin developed by our group that closely mimics human pathology. This application is based on our preliminary data that IL-1 signaling is required to mediate intraamniotic endotoxin induced lung inflammatory responses and that the sheep fetus adapts to repeated exposures to intraamniotic endotoxin with decreased monocyte responsiveness to endotoxin. In Specific Aim 1 we will define the relative contributions of the chorioamnion, lung and gastrointestinal tract to development of FIRS induced by endotoxin. We will utilize fetal surgical methods developed by our group to isolate each of the organs. In Specific Aim 2 we will test if intraamniotic IL-1 causes FIRS and determine the requirement of IL-1 signaling in LPS induced FIRS using an IL-1 receptor antagonist. In Specific Aim 3 we will evaluate fetal adaptation and endotoxin tolerance to repeated exposures of intraamniotic endotoxin. Our long term goals are to understand the mechanisms of systemic inflammation and organ injury responses following exposure to chorioamnionitis. This grant will provide a framework to understand the problem of FIRS at a whole animal level. This work will provide insights necessary to the development of therapeutic strategies such as selective intraamniotic anti-inflammatory therapy to improve outcomes in preterm infants exposed to chorioamnionitis. PUBLIC HEALTH RELEVANCE: Chorioamnionitis and the associated systemic inflammatory responses cause significant morbidity in preterm neonates and are a major public health problem in this population. This grant will define the mechanisms of systemic inflammatory response in a sheep model of chorioamnionitis induced by intraamniotic endotoxin. This knowledge will be essential to developing treatment approaches aimed at improving preterm infant outcomes.