Experimental Model for Chorioamnionitis and Prematurity

在美国，早产是新生儿发病率和死亡率的主要原因。宫内感染是早产的一个重要的潜在的可治疗的原因，并与新生儿脑白质损伤和脑性瘫痪的风险增加有关。然而，感染导致早产和/或脑瘫的机制仍然是推测的，治疗策略在很大程度上还没有得到测试，因为感染后不能纵向研究人类。我们建议使用妊娠120-130天的恒河猴进行实验性宫内感染的实验研究(Gravett等人，Am J Obstet and Gynecol；171：1660-1667,1994)，以研究感染、细胞因子、前列腺素、类固醇激素、细胞因子拮抗剂、早产和新生儿脑白质损伤之间的时间和数量关系，以开发有效的干预策略。术后稳定下来后，我们将：(1)将B组链球菌(GBS)接种到羊水中，建立宫内感染和早产。将持续监测子宫收缩能力，并定期采集羊水和母胎血样本(1-4毫升)，用于分析二十烷类、类固醇激素、细胞因子、基质金属蛋白酶和用于微生物研究；(2)在没有感染的情况下，联合使用抗生素和有效的促炎细胞因子产生抑制剂(地塞米松、IL-10)和前列腺素(吲哚美辛)，以确定下调细胞因子/前列腺素级联反应及相关子宫活动的最有效干预措施；(3)在无感染的情况下，通过留置导管将促炎症细胞因子IL-1β注入羊膜腔。在无感染的情况下输注IL-1β之前，将使用特定的新型促炎细胞因子抑制剂(IL-1ra和sTNF-R1PEG)来识别其他潜在有用的免疫调节剂。在剖宫产术中将获得蜕膜、胎膜、组织和脑的样本，用于微生物学、组织病理学研究、细胞因子的免疫组织化学、细胞因子和PGHS-2的定位和定量mRNA的测定。将对胎儿大脑进行检查，以确定与脑白质损伤相关的细胞凋亡增加。产后将用流式细胞仪对羊水和气管抽吸物中的白细胞进行检测，母亲将接受适当的抗生素治疗，以消除生殖道中的GBS并返回菌落。这些研究将阐明感染相关早产的病理生理学，并将提出有效的干预策略。

Prematurity is the leading cause of neonatal morbidity and mortality in the United States. Intrauterine infections are an important, and potentially treatable cause of prematurity, and are associated with increased risk of neonatal white matter lesions of the brain and cerebral palsy. However, the mechanisms by which infection leads to prematurity and/or cerebral palsy remain speculative and treatment strategies untested largely because humans cannot be longitudinally studied following infection. We propose to use chronically instrumented pregnant rhesus monkeys at 120-130 day gestation with experimental intrauterine infection, as previously described (Gravett et al, Am J Obstet and Gynecol; 171:1660-1667,1994) to study the temporal and quantitative relationships among infection, cytokines, prostaglandins, steroid hormones, cytokine antagonists, preterm labor, and neonatal white matter lesions of the brain in order to develop effective interventional strategies. After postoperative stabilization in a tether, we will; (1) inoculate Group B Streptococci (GBS) into the amniotic fluid to establish intrauterine infection and preterm labor. Uterine contractility will be continuously monitored and periodic samples of amniotic fluid and maternal and fetal blood (1-4 cc) will be obtained for assays of eicosanoids, steroid hormones, cytokines, matrix metalloproteinases and for microbial studies; (2) utilize antibiotics with and without potent inhibitors of proinflammatory cytokine production (dexamethasone,IL-10) o prostaglandin production (indomethacin) to ascertain the most effective intervention to down-regulate the cytokine/prostaglandin cascade and associated uterine activity; (3) infuse proinflammatory cytokine IL-1beta into the amniotic cavity through indwelling catheters in the absence of infection. Prior to infusion of IL-1beta in the absence of infection, specific novel proinflammatory cytokine inhibitors (IL-1ra and sTNF-R1 PEG) will be used to identify other potentially useful immunomodulators. Samples of the decidua, fetal membranes, tissues, and brain will be obtained at cesarean section for microbiologic, histopathologic studies, immunohistochemistry for cytokines, localization and quantitation of mRNA for cytokines and PGHS-2. Fetal brain will be examined for increased apoptosis associated with white matter lesions. Leukocytes in amniotic fluid and tracheal aspirates will be assessed by flow cytometry Postpartum, the mother will be treated with appropriate antibiotics to eradicate the GBS from the genital tract and returned to the colony. These studies will clarify the pathophysiology of infection-associated preterm labor and will suggest effective interventional strategies.