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）： 已知胎儿暴露会影响童年和以后生活的肺功能。尽管大约有7％的出生物被归类为晚期（32o-366 wks妊娠的出生），而这些婴儿在儿童期肺部相关问题的风险增加，但该人群的肺部结果最少。胎儿暴露于绒毛膜炎（炎症/感染）会对肺发育产生不利影响，并调节胎儿免疫功能。人类中与胎儿炎症/慢性绒毛膜膜炎相关的最常见生物是尿素质量属。我们假设胎儿​​暴露于尿素倍率SPP会调节免疫反应，并增加晚期婴儿儿童早期肺部疾病的风险。我们将通过一项临床研究和胎儿绒毛膜绒毛膜炎的临床研究和平行的实验研究来检验这一假设。临床研究将基于尿素质量属的培养物和绒毛膜炎的组织病理学选择晚期早产婴儿的同类。胎儿炎症反应将通过脐带血，分子表型和脐带血单核细胞中的细胞因子/趋化因子谱进行评估，树突状细胞将表征胎儿免疫状态。暴露和未暴露的晚期婴儿的尿素成倍率将在9 MOS和2年内进行肺部健康评估，并在9个MOS处进行肺功能测试，以评估肺癌。在平行的实验中，我们将表征胎儿绵羊对肿瘤炎的炎症和免疫调节反应，这是由U. parvum注入的肿瘤内注射引起的。我们将探索对多带抗原（MBA）变异性的体内炎症/免疫反应，因为在体外已将MBA视为U. Parvum的毒力因子。我们将表征妊娠年龄和从暴露到分娩的间隔如何调节对U. Parvum的胎儿免疫和炎症反应。我们将允许U. Parvum裸露的胎儿在2周和2个MOS时传递和测量肺功能和结构。实验是创新的，因为我们将重点关注晚期婴儿（大量研究的人群），以定义出生时的免疫状态。我们将与肺部炎和绒毛膜炎与肺部结局以及免疫学测量有关。我们将使用绵羊中绒毛膜膜炎的临床相关模型来评估人类不可能的免疫调节方面。结果将首次与肺部结局进行特定和常见的胎儿炎症暴露联系。这项研究将由一个经验丰富的研究人员团队对项目的每个组成部分进行专业知识：新生儿人和胎儿绵羊的尿素质量SPP，免疫和炎症反应的生物学，绒毛膜炎的动物模型以及儿童肺部评估。公共卫生相关性：胎儿暴露于绒毛膜炎，增加了早产儿儿童期支气管肺发育异常和肺部异常的风险。晚期婴儿在童年时期增加了肺部疾病，但人口众多。我们将通过炎症，免疫和肺结局评估评估人类和相关的绵羊模型中最常见的胎儿炎症暴露 - 尿素SPMA相关的绒毛膜炎。结果将提供信息，以识别有风险的婴儿并制定预防和治疗策略。 （抽象的结尾）