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: 7766216
• 负责人: SUHAS KALLAPUR
• 金额: $ 30.93万
• 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/7766216
• 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; 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-1 Receptors; 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; fetus surgery; gastrointestinal; improved; infant outcome; insight; monocyte; mortality; novel; peripheral blood; public health relevance; 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）：胎儿膜中的绒毛膜炎或炎症存在于30周之前出生的早产儿的70％，这是该人群中发病率和死亡的主要原因。胎儿炎症反应综合征（FIR）存在于暴露于绒毛膜炎炎的早产儿中，并被认为是绒毛膜炎诱导的胎儿损伤反应的介体。尽管许多流行病学研究暗示FIR是早产新生儿不良神经，胃肠道和肺癌的强大危险因素，但对FIR的机制或发病机理知之甚少。在理解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。该提案将检验以下假设：胎儿暴露于绒毛膜瘤造成系统性炎症反应，该反应是由IL-1信号在羊膜室中引发的，并且受系统性的先天免疫反应调节。这些实验将利用由我们的小组开发的羊膜内内毒素引起的绒毛膜瘤的早产胎羊模型，这些模型密切模仿了人类病理。该应用是基于我们的初步数据，即需要IL-1信号传导来介导氨内毒素诱导的肺部炎症反应，并且绵羊胎儿适应对铝内内毒素的反复暴露，而单核细胞对内毒素的反应降低。在特定目标1中，我们将定义绒毛膜膜，肺和胃肠道对内毒素诱导的FIR的相对贡献。我们将利用小组开发的胎儿手术方法来隔离每个器官。在特定的目标2中，我们将测试使用IL-1受体拮抗剂在LPS诱导的FIR中确定IL-1信号传导的需求。在特定的目标3中，我们将评估胎儿适应性和内毒素的耐受性，可反复暴露于氨内毒素内毒素。我们的长期目标是了解暴露于绒毛膜炎后系统性炎症和器官损伤反应的机制。该赠款将提供一个框架，以了解整个动物一级的FIR问题。这项工作将为开发治疗策略（例如选择性羊水抗炎疗法）提供必要的见解，以改善暴露于绒毛膜炎的早产儿的预后。公共卫生相关性：绒毛膜膜炎和相关的全身性炎症反应在早产新生儿引起了显着的发病率，并且是该人群的主要公共卫生问题。该赠款将定义由羊膜内内毒素诱导的绒毛膜炎模型中系统性炎症反应的机制。这些知识对于开发旨在改善早产婴儿结果的治疗方法至关重要。