Mechanisms of Fetal Inflammatory Response Syndrome Induced by Chorioamnionitis

绒毛膜羊膜炎诱发胎儿炎症反应综合征的机制

• 批准号: 8049088
• 负责人: SUHAS KALLAPUR
• 金额: $ 31.06万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-03 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049088
• 关键词: Amniotic Fluid; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Birth; Blood; Blood Vessels; Chronic; Clinical Trials; Collection; Data; Development; Endothelium; Endotoxins; Epidemiologic Studies; Epithelium; Equilibrium; Exposure to; Fetal Development; Fetal Lung; Fetal Membranes; Fetus; Gastrointestinal tract structure; Goals; Grant; Health; Human; Human Pathology; Immune response; Immune system; Infant; Infection; Infection of amniotic sac and membranes; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Interleukin-1; Interleukin-6; Knowledge; Leukocytes; Lipopolysaccharides; Liver; Lung; Lung Inflammation; Measures; Mediating; Mediator of activation protein; Methods; Modeling; Morbidity - disease rate; Neurologic; Neutrophilia; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Perinatal Exposure; Plasma; Population; Pregnancy; Premature Birth; Premature Infant; Process; Public Health; Recombinants; Relative (related person); Research Proposals; Risk; Risk Factors; Role; Route; Saline; Sepsis; Sheep; Signal Transduction; Source; Syndrome; Testing; Thymus Gland; Tissues; Trachea; Translational Research; Vascular Endothelium; Work; base; body system; cytokine; fetal; fetal blood; fetus surgery; gastrointestinal; improved; infant outcome; insight; monocyte; mortality; novel; peripheral blood; receptor; research study; response; response to injury; therapeutic development

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.

描述（由申请人提供）：约 70% 妊娠 30 周前出生的早产儿患有绒毛膜羊膜炎或胎膜炎症，是该人群发病率和死亡率的主要原因。约 50% 暴露于绒毛膜羊膜炎的早产儿中存在胎儿炎症反应综合征 (FIRS)，并且被认为是绒毛膜羊膜炎引起的胎儿损伤反应的介质。尽管许多流行病学研究表明 FIRS 是早产儿神经、胃肠道和肺部不良结局的一个强烈危险因素，但人们对 FIRS 的机制或发病机制知之甚少。了解 FIRS 如何启动或发出信号的过程中的一个主要障碍是缺乏合适的动物模型。该提案将检验以下假设：胎儿暴露于绒毛膜羊膜炎会诱发全身炎症反应，该反应由羊膜腔内的 IL-1 信号传导引发，并受到全身先天免疫反应的调节。实验将利用我们小组开发的羊膜内内毒素诱导的早产胎羊绒毛膜羊膜炎模型，该模型非常模仿人类病理学。该应用基于我们的初步数据，即介导羊膜内内毒素诱导的肺部炎症反应需要IL-1信号传导，并且羊胎儿适应重复暴露于羊膜内内毒素，单核细胞对内毒素的反应性降低。在具体目标 1 中，我们将定义绒毛膜羊膜、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来分离每个器官。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 信号传导的需求。在具体目标 3 中，我们将评估胎儿对羊膜内内毒素反复暴露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炎症和器官损伤反应的机制。这笔赠款将提供一个框架来理解整个动物层面的 FIRS 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结局。公共卫生相关性：绒毛膜羊膜炎和相关的全身炎症反应导致早产儿显着发病，是该人群的主要公共卫生问题。该资助将定义羊膜内内毒素诱导的绒毛膜羊膜炎绵羊模型的全身炎症反应机制。这些知识对于开发旨在改善早产儿结局的治疗方法至关重要。