Postnatal Consequences of Fetal Inflammation

胎儿炎症的产后后果

• 批准号: 7111958
• 负责人: ALAN H JOBE
• 金额: $ 17.51万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111958
• 关键词: Mycoplasmatales; antigens; birth; embryo /fetus; endotoxins; inflammation; lung; lymphocyte; model; monocyte; sheep

DESCRIPTION (provided by applicant): In response to the RFA "Innovative Grants on Immune Tolerance," we propose to test the hypothesis that antenatal exposure to inflammation induces innate immune responses via the fetal lungs that will reprogram postnatal airway responsiveness and immune status. The majority of very low birth weight preterm infants are exposed to chronic indolent chorioamnionitis (inflammation) that can alter lung development and result in bronchopulmonary dysplasia. Many near-term and term infants also are exposed to antenatal infection. We have developed chronic chorioamnionitis models in fetal sheep using intraamniotic injections of endotoxin or live Ureaplasma, the organism most frequently associated with preterm delivery. Fetal sheep exposed to endotoxin develop innate immune paralysis of lung and systemic monocytes as well as other indicators of immune modulation. We will cause chronic chorioamnionitis and lung inflammation in fetal sheep using endotoxin or Ureaplasma parvum. We will evaluate monocyte and lymphocyte responses in the fetus at term in groups of animals. We will randomize other groups of animals to spontaneous delivery and sensitization with house dust mite antigen as newborns. We will then evaluate airway reactivity and immune status at 8 wks of age. The evaluations will include characterization and responses to stimulation in vitro of lymphocytes and monocytes from the blood, lung tissue, caudal mediastinal lymph nodes, spleen and thymus. The experiments will directly test the effects of two clinically relevant fetal exposures on postnatal lung sensitization and function. Relevance to public health: Many preterm and term human fetuses are exposed to chorioamnionitis/ inflammation which can cause profound immune modulation in animal models. Preterms have an increased risk of developing asthma/airway reactivity and the incidence of asthma is increasing in children. This research will use clinically relevant prenatal exposures and postnatal sensitization to establish under controlled conditions any link between antenatal inflammation and the hygiene hypothesis.

描述（由申请人提供）：为了响应 RFA“免疫耐受创新资助”，我们建议测试以下假设：产前暴露于炎症会通过胎儿肺部诱导先天免疫反应，从而重新编程产后气道反应性和免疫状态。大多数出生体重极低的早产儿都患有慢性惰性绒毛膜羊膜炎（炎症），这种疾病会改变肺部发育并导致支气管肺发育不良。许多近足月和足月婴儿也容易受到产前感染。我们通过羊膜内注射内毒素或活脲原体（最常与早产相关的生物体）在胎羊中建立了慢性绒毛膜羊膜炎模型。暴露于内毒素的胎羊会出现肺和全身单核细胞的先天免疫麻痹以及其他免疫调节指标。我们将使用内毒素或微小脲原体引起胎羊慢性绒毛膜羊膜炎和肺部炎症。我们将在动物组中评估足月胎儿的单核细胞和淋巴细胞反应。我们将随机分配其他组的动物进行自然分娩，并在新生儿时使用屋尘螨抗原进行致敏。然后我们将在 8 周龄时评估气道反应性和免疫状态。评估将包括来自血液、肺组织、尾部纵隔淋巴结、脾脏和胸腺的淋巴细胞和单核细胞的特征和对体外刺激的反应。这些实验将直接测试两种临床相关的胎儿暴露对出生后肺部敏化和功能的影响。与公共健康的相关性：许多早产和足月人类胎儿会遭受绒毛膜羊膜炎/炎症，这可能会在动物模型中引起严重的免疫调节。早产儿发生哮喘/气道反应性的风险增加，并且儿童哮喘的发病率也在增加。这项研究将利用临床相关的产前暴露和产后致敏，在受控条件下建立产前炎症和卫生假设之间的联系。