Late Preterm Birth, Ureaplasma Species and Childhood Lung Disease

描述（由申请人提供）： 已知胎儿暴露会影响儿童期和以后生活中的肺功能。尽管约7%的新生儿被归类为晚期早产（妊娠320 -366周的新生儿），并且这些婴儿在儿童期发生肺部相关问题的风险增加，但对这一人群的肺部结局研究很少。胎儿暴露于绒毛膜炎（炎症/感染）可对肺发育产生不利影响，并调节胎儿免疫功能。与人类胎儿炎症/慢性绒毛膜炎相关的最常见微生物是脲原体属。我们推测胎儿暴露于脲原体可调节免疫反应，增加晚期早产儿在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与U.胎羊细小绒毛膜炎。临床研究将根据支原体培养和绒毛膜炎组织病理学选择晚期早产儿队列。胎儿炎症反应将通过脐带血中的细胞因子/趋化因子谱、分子表型和脐带血单核细胞的免疫调节进行评价，树突状细胞将表征胎儿免疫状态。暴露于和未暴露于脲原体的晚期早产儿将在9个月和2岁时进行肺健康评估，并在9个月时进行肺功能检查，以评价肺部结局。在平行实验中，我们将描述胎羊对羊膜内注射U。小的我们将探讨体内炎症/免疫反应的多带抗原（MBA）的变异性，因为MBA已被确定为在体外毒力因子的U。小的我们将描述胎龄和从暴露到分娩的间隔如何调节胎儿对U。小的我们将允许你。在2周龄和2月龄时，暴露胎仔以分娩并测量免疫状态、肺功能和结构。这些实验是创新的，因为我们将重点放在晚期早产儿，一个大的未充分研究的人口，以确定出生时的免疫状态。我们将胎儿脲原体暴露和绒毛膜炎与肺部结局和免疫学测量结果相关联。我们将使用临床相关的绵羊绒毛膜炎模型来评估人类不可能的免疫调节方面。研究结果将首次将特定和常见的胎儿炎症暴露与肺部结局联系起来。该研究将由一组经验丰富的研究人员进行，他们对该项目的每个组成部分都具有专业知识：脲原体属的生物学，新生儿和胎羊的免疫和炎症反应，绒毛膜炎的动物模型以及儿童的肺部评估。公共卫生相关性：胎儿暴露于绒毛膜炎可增加极早产儿儿童期支气管肺发育不良和肺异常的风险。晚期早产儿在儿童期肺部疾病增加，但这是一个庞大且研究很少的人群。我们将通过炎症、免疫和肺部结局评估，在人类和相关绵羊模型中评价最常见的胎儿炎症暴露-脲原体属相关绒毛膜炎。研究结果将提供信息，以确定处于危险中的婴儿，并制定预防和治疗策略。(End摘要）

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)