Late Preterm Birth, Ureaplasma Species and Childhood Lung Disease

晚期早产、解脲支原体和儿童肺病

• 批准号: 7713829
• 负责人: ALAN H JOBE
• 金额: $ 51.89万
• 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: 2009-09-24 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7713829
• 关键词: Affect; Age; Age-Months; Alveolar Macrophages; Amniocentesis; Amniotic Fluid; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Asthma; Bacteria; Biology; Birth; Bronchoalveolar Lavage; Bronchopulmonary Dysplasia; CD80 gene; Caring; Cells; Child; Childhood; Chronic; Clinical; Clinical Research; Dendritic Cells; Disease; Drug usage; Elderly; Exposure to; Fetal Membranes; Fetus; Freezing; Gestational Age; Grant; Growth; HLA-DR Antigens; Health; Health Surveys; Histologic; Histopathology; Human; Human Pathology; Hydrogen Peroxide; Hygiene; IL8 gene; Immune; Immune response; Immune system; Immunologics; In Vitro; Infant; Infection; Infection of amniotic sac and membranes; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Interleukin-6; Length; Link; Lung; Lung Inflammation; Lung diseases; Measurement; Measures; Mediastinal lymph node group; Modeling; Mononuclear; Mothers; Mycoplasma; Neonatal; Newborn Infant; Organism; Outcome; Outcome Assessment; Perinatal Exposure; Plasma; Population; Population Study; Pregnancy; Premature Birth; Premature Infant; Production; Pulmonary function tests; Questionnaires; Reporting; Research; Research Personnel; Respiratory physiology; Risk; Risk Factors; Role; Severities; Sheep; Signaling Molecule; Structure; TLR2 gene; TLR3 gene; TLR4 gene; Testing; Time; Umbilical Cord Blood; Umbilical cord structure; Ureaplasma; Variant; Virulence; Virulence Factors; Virulent; abstracting; base; chemokine; cigarette smoking; clinically relevant; cohort; comparison group; cytokine; early childhood; experience; fetal; human disease; immune function; immunoregulation; in vivo; innovation; insight; lung development; mRNA Expression; macrophage; maternal diabetes; methacholine; molecular phenotype; monocyte; postnatal; prenatal; public health relevance; research study; response; surfactant; treatment strategy

DESCRIPTION (provided by applicant): Fetal exposures are known to influence lung function in childhood and later life. Although about 7% of all births are categorized as late-preterm (births at 32o-366 wks gestation) and these infants are at increased risk for lung related problems in childhood, this population has been minimally studied for lung outcomes. Fetal exposure to chorioamnionitis (inflammation/infection) can adversely affect lung development and modulate fetal immune function. The most frequent organism associated with fetal inflammation/chronic chorioamnionitis in the human is Ureaplasma spp. We hypothesize that fetal exposure to Ureaplasma spp modulates immune responses and increases the risk of lung disease in early childhood in late-preterm infants. We will test this hypothesis with a clinical study and a parallel experimental study with U. parvum chorioamnionitis in fetal sheep. The clinical study will select cohorts of late preterm infants based on cultures for Ureaplasma spp, and histopathology for chorioamnionitis. Fetal inflammatory responses will be evaluated by cytokine/chemokine profiles in cord blood, molecular phenotypes and immune modulation by cord blood monocytes, and dendritic cells will characterize fetal immune status. The ureaplasma exposed and unexposed late-preterm infants will have lung health assessments at 9 mos and 2 yrs, and pulmonary function tests at 9 mos to evaluate lung outcomes. In parallel experiments we will characterize the inflammatory and immune modulatory responses of fetal sheep to the chorioamnionitis caused by intra-amniotic injection of U. parvum. We will explore the in vivo inflammatory/immune responses to multi-banded antigen (MBA) variability because MBA has been identified in vitro as the virulence factor for U. parvum. We will characterize how gestational age and interval from exposure to delivery modulate the fetal immune and inflammatory responses to U. parvum. We will allow U. parvum exposed fetuses to deliver and measure immune status lung function and structure at 2 wks and 2 mos of age. The experiments are innovative be cause we will focus on late-preterm infants, a large understudied population, to define immune status at birth. We will correlate of fetal ureaplasma exposure and chorioamnionitis with pulmonary outcomes and with immunologic measurements. We will use a clinically relevant model of chorioamnionitis in sheep to evaluate aspects of immune modulation that are not possible in humans. The results will link for the first time a specific and common fetal inflammatory exposure with lung outcomes. The research will be performed by a team of experienced investigators with expertise for each component of the project: the biology of Ureaplasma spp, immune and inflammatory responses in the newborn human and fetal sheep, animal models of chorioamnionitis, and pulmonary assessments of children. PUBLIC HEALTH RELEVANCE: Fetal exposures to chorioamnionitis increase the risks for bronchopulmonary dysplasia and lung abnormalities in childhood in very preterm infants. Late-preterm infants have increased lung disease in childhood, but are a large and minimally studied population. We will evaluate the most common fetal inflammatory exposure - Ureaplasma spp associated chorioamnionitis - in the human and in a relevant sheep model by inflammatory, immune, and lung outcome assessments. The results will provide the information to identify infants at risk and to develop preventative and treatment strategies. (End of Abstract)

描述(由申请人提供)： 众所周知，胎儿暴露会影响儿童时期和以后的生活中的肺功能。虽然大约7%的新生儿被归类为晚早产(孕周320-366周出生)，而且这些婴儿在儿童时期患肺相关问题的风险增加，但对这一人群的肺结果进行了最少的研究。胎儿暴露于绒毛膜羊膜炎(炎症/感染)可对肺部发育和调节胎儿免疫功能产生不利影响。在人类中，与胎儿炎症/慢性绒毛膜羊膜炎相关的最常见的微生物是解脲支原体。我们假设胎儿暴露于解脲支原体可调节免疫反应，并增加晚期早产儿儿童早期肺部疾病的风险。我们将通过一项临床研究和一项平行的实验研究来验证这一假设，该研究是关于羊胎毛滴虫绒毛膜羊膜炎的。这项临床研究将根据解脲支原体培养和绒毛膜羊膜炎的组织病理学来选择晚期早产儿的队列。胎儿的炎症反应将通过脐带血中细胞因子/趋化因子的变化、分子表型和脐血单核细胞的免疫调节来评估，树突状细胞将表征胎儿的免疫状态。解脲支原体暴露和未暴露的晚期早产儿在9个月和2岁时进行肺健康评估，并在9个月时进行肺功能测试，以评估肺结果。在平行实验中，我们将描述胎羊对羊膜内注射解脲支原体引起的绒毛膜羊膜炎的炎症和免疫调节反应。我们将探索体内对多带抗原(MBA)可变性的炎症/免疫反应，因为MBA在体外已被确定为微小支原体的毒力因子。我们将描述胎龄和从接触到分娩的间隔时间如何调节胎儿对解脲支原体的免疫和炎症反应。我们将允许暴露在微小支原体下的胎儿在2周和2个月龄时分娩并测量免疫状态、肺功能和结构。这些实验是创新的，因为我们将关注晚早产儿，这是一个庞大的未被研究的群体，以确定出生时的免疫状态。我们会将胎儿解脲支原体暴露和绒毛膜羊膜炎与肺部结局和免疫学测量相关联。我们将使用绵羊绒毛膜羊膜炎的临床相关模型来评估在人类中不可能实现的免疫调节方面。这一结果将首次将特定和常见的胎儿炎症暴露与肺部结果联系起来。这项研究将由一组经验丰富的研究人员进行，他们对项目的每个组成部分都有专业知识：解脲支原体的生物学、新生儿和胎羊的免疫和炎症反应、绒毛膜羊膜炎的动物模型以及儿童的肺部评估。公共卫生相关性：在极早产儿中，胎儿暴露于绒毛膜羊膜炎会增加儿童时期支气管肺发育不良和肺异常的风险。晚期早产儿在童年时会增加肺部疾病，但这是一个很大的研究人群，研究的对象也很少。我们将通过炎症、免疫和肺结果评估来评估最常见的胎儿炎性暴露--解脲支原体相关性绒毛膜羊膜炎--在人类和相关的绵羊模型中。研究结果将为识别处于危险中的婴儿以及制定预防和治疗策略提供信息。(摘要结束)