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)

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