Postnatal Consequences of Fetal Inflammation

描述（由申请人提供）：作为对RFA“免疫耐受创新资助”的回应，我们提议测试一种假设，即产前暴露于炎症会通过胎儿肺部诱导先天免疫反应，从而重新编程出生后气道反应和免疫状态。大多数极低出生体重的早产儿暴露于慢性无痛绒毛膜羊膜炎（炎症），可改变肺发育并导致支气管肺发育不良。许多短期和足月婴儿也暴露于产前感染。我们利用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。我们将在胎羊中使用内毒素或细小脲原体引起慢性绒毛膜羊膜炎和肺部炎症。我们将在动物群中评估足月胎儿的单核细胞和淋巴细胞反应。我们将随机选择其他动物组作为新生儿进行自然分娩和屋尘螨抗原敏化。然后我们将在8周龄时评估气道反应性和免疫状态。评估将包括体外对血液、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刺激的表征和反应。本实验将直接测试两种临床相关的胎儿暴露对产后肺致敏和功能的影响。与公共卫生的相关性：许多早产儿和足月人类胎儿暴露于绒毛膜羊膜炎/炎症，在动物模型中可引起深刻的免疫调节。早产儿患哮喘/气道反应性的风险增加，儿童哮喘的发病率也在增加。本研究将使用临床相关的产前暴露和产后致敏，在控制条件下建立产前炎症和卫生假说之间的任何联系。

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.