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出现在30周前出生的早产儿中约70%，是导致这一人群发病率和死亡率的主要因素。胎儿炎性反应综合征(FIRS)存在于暴露于绒毛膜羊膜炎的早产儿中的约50%，被认为是绒毛膜羊膜炎引起的胎儿损伤反应的媒介。尽管许多流行病学研究表明FIRS是早产儿神经系统、胃肠道和肺部不良结局的重要危险因素，但对FIFS的机制或发病机制知之甚少。在理解冷杉是如何启动或发出信号的过程中，一个主要的绊脚石是缺乏合适的动物模型。这一建议将检验一种假说，即胎儿暴露于绒毛膜羊膜炎会诱导全身炎症反应，该反应由羊膜腔内的IL-1信号启动，并受全身先天免疫反应的调节。本实验将利用本课题组建立的羊膜内毒素诱导的早产胎羊绒毛膜羊膜炎模型，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，即IL-1信号需要介导羊膜内毒素诱导的肺炎性反应，绵羊胎儿适应羊膜内毒素重复暴露，单核细胞对内毒素的反应性降低。在具体目标1中，我们将确定绒毛羊膜、肺和胃肠道在内毒素诱导的FIRS发生中的相对作用。我们将使用我们团队开发的胎儿外科方法来分离每个器官。在特定的目标2中，我们将测试羊膜腔内IL-1是否导致FIRS，并使用IL-1受体拮抗剂来确定在脂多糖诱导的FIRS中对IL-1信号的需求。在具体目标3中，我们将评估胎儿对反复羊膜内毒素暴露的适应性和内毒素耐受性。我们的长期目标是了解绒毛膜羊膜炎暴露后全身炎症和器官损伤反应的机制。这笔赠款将提供一个框架，在整个动物水平上理解冷杉问题。这项工作将为制定治疗策略提供必要的见解，例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。

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.