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）：响应RFA“因免疫耐受性创新赠款”，我们建议检验以下假设：产前暴露于炎症会通过胎儿肺导致先天免疫反应，这些胎儿将通过胎儿肺进行重新编程后气道反应后反应和免疫状态。大多数非常低的出生体重早产儿都暴露于慢性酸性绒毛膜炎（炎症），可改变肺发育并导致支气管肺发育不良。许多近期和期限婴儿也暴露于产前感染。我们已经使用内毒素内注射或活尿素超代的羊膜绵羊中开发了慢性绒毛膜膜炎模型，这是最常见的生物体与早产相关的生物。暴露于内毒素的胎儿绵羊会产生肺和全身单核细胞的先天免疫瘫痪以及免疫调节的其他指标。我们将使用内毒素或尿素质量par鼠引起胎儿绵羊的慢性绒毛膜炎和肺部炎症。我们将在胎儿中评估胎儿中的单核细胞和淋巴细胞反应。我们将将其他动物群随机以自发递送和敏感性，以新生儿的粉尘螨抗原作为新生儿。然后，我们将评估8周龄的气道反应性和免疫状态。评估将包括对血液，肺组织，尾纵隔淋巴结，脾脏和胸腺的淋巴细胞和单核细胞体外刺激的反应。该实验将直接测试两种临床相关的胎儿暴露对产后肺敏化和功能的影响。与公共卫生有关：许多早产和人类胎儿都暴露于绒毛膜炎/炎症中，这可能会导致动物模型中的严重免疫调节。早产的风险增加患哮喘/气道反应性，儿童的哮喘发病率正在增加。这项研究将使用临床上相关的产前暴露和产后敏化，以在受控条件下建立产前炎症与卫生假说之间的任何联系。