Mechanisms of Fetal Inflammatory Response Syndrome Induced by Chorioamnionitis

描述（由申请方提供）：妊娠30周前出生的早产儿中约有70%存在绒毛膜炎或胎膜炎症，是该人群发病率和死亡率的主要原因。胎儿炎症反应综合征（FIRS）存在于约50%的早产儿暴露于绒毛膜炎，被认为是绒毛膜炎诱导的胎儿损伤反应的介导者。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一个强有力的危险因素，但对FIRS的机制或发病机制知之甚少。在理解FIRS如何启动或发出信号的过程中，一个主要的绊脚石是缺乏适当的动物模型。该提议将检验胎儿暴露于绒毛膜炎诱导全身炎症反应的假设，该全身炎症反应由羊膜腔中的IL-1信号传导启动，并由全身先天免疫反应调节。本实验将利用我们小组开发的羊膜内毒素诱导的早产胎羊绒毛膜炎模型，该模型非常模拟人类病理学。该应用基于我们的初步数据，即IL-1信号传导是介导羊膜内毒素诱导的肺部炎症反应所必需的，并且绵羊胎儿适应反复暴露于羊膜内毒素，单核细胞对内毒素的反应性降低。在具体目标1中，我们将确定绒毛膜羊膜、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手术方法分离每个器官。在具体目标2中，我们将测试羊膜内IL-1是否引起FIRS，并使用IL-1受体拮抗剂确定LPS诱导的FIRS中IL-1信号传导的需求。在具体目标3中，我们将评价胎儿对反复暴露于羊膜内毒素的适应性和内毒素耐受性。我们的长期目标是了解接触绒毛膜炎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，以了解整个动物水平的FIRS问题。这项工作将提供必要的见解，如选择性羊膜内抗炎治疗，以改善暴露于绒毛膜炎的早产儿的治疗策略的发展。公共卫生相关性：绒毛膜炎和相关的全身炎症反应导致早产儿的显著发病率，并且是该人群的主要公共卫生问题。该基金将确定羊膜内毒素诱导的绒毛膜炎绵羊模型的全身炎症反应机制。这些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.