Preterm Labor and Fetal Sequelae: Role of Ureaplasmas

描述(由申请人提供)：本研究计划的目标是评估抗生素和抗炎治疗对羊膜内感染微小解脲支原体(前1号解脲支原体)的流动、慢性插管妊娠恒河猴早产和早产相关后遗症(即胎儿肺损伤)的疗效。我们的假设是，产前使用大环内酯类抗生素联合抗炎药和免疫调节剂治疗宫内解脲支原体感染将抑制早产，推迟早产，改善或预防胎儿/新生儿肺部疾病生理研究以及对宫内和胎儿组织的细胞和分子研究将解决以下问题：(1)阿奇霉素联合前列腺素合成抑制剂(吲哚美辛)和地塞米松治疗是否抑制羊膜内微生物生长并下调细胞因子/前列腺素级联反应？(2)这些干预措施是否预防早产和胎儿肺部疾病而没有不良的胎儿副作用？比较NO治疗、抗生素治疗以及抗生素/抗炎联合治疗对早产和胎儿后遗症的影响。将确定一些终点，以建立解脲支原体感染、早产、胎儿肺损伤和治疗反应(包括潜在的胎儿副作用(例如，脑室出血、小肠结肠炎))之间的联系。连续记录子宫收缩能力将与羊水中前列腺素、细胞因子、白细胞、基质金属蛋白酶以及母体、胎儿和羊水中阿奇霉素的水平相关。将对羊水、血液和胎儿组织进行解脲支原体的定量培养和聚合酶链式反应。组织细胞因子mRNA的定量将采用实时定量聚合酶链式反应(Real-time PCR)。胎儿肺损伤将通过组织病理学和免疫组织化学方法以及肺形态计量学进行评估。将对胃肠道、脑膜和大脑进行炎症检查。脑白质中少突胶质细胞前体细胞和其他类型细胞的死亡将通过免疫组织化学方法和细胞凋亡检测来评估。这项工作的独特之处在于，它在一个已建立的宫内感染的非人类灵长类动物模型中使用了组合干预策略。这一结果应该阐明解脲支原体在早产儿中的因果作用，并导致临床治疗的进步。

DESCRIPTION (provided by applicant): The objectives of this Research Plan are to assess the efficacy of antibiotic and anti-inflammatory therapy on preterm labor and relevant sequelae of prematurity (i.e., fetal lung injury) in mobile, chronically catheterized pregnant rhesus monkeys infected intraamniotically with Ureaplasma parvum (formerly U. urealyticum serovar 1). It is our hypothesis that prenatal treatment of intrauterine ureaplasmal infection with an intravenous macrolide antibiotic combined with an anti-inflammatory agent and an immunomodulator will inhibit preterm labor, delay premature delivery, and ameliorate or prevent fetal/neonatal lung disease Physiological studies together with cellular and molecular studies of intrauterine and fetal tissues will address the following questions: (1) Does therapy with azithromycin combined with a prostaglandin synthesis inhibitor (indomethacin) and with dexamethasone inhibit intraamniotic microbial growth and downregulate the cytokine/prostaglandin cascade? (2) Do these interventions prevent preterm labor and fetal lung disease without adverse fetal side-effects? The effect of no treatment, antibiotic therapy, and combined antibiotic/anti-inflammatory therapy on preterm labor and fetal sequelae will be compared. A number of endpoints will be ascertained to establish links among ureaplasma infections, preterm labor, fetal lung injury and the response to therapy including potential fetal side-effects (e.g., intraventricular hemorrhage, enterocolitis). Continuous recordings of uterine contractility will be correlated with amniotic fluid levels of prostaglandins, cytokines, leukocytes, MMPs and maternal, fetal and amniotic fluid levels of azithromycin. Quantitative cultures and PCR for ureaplasmas will be performed on amniotic fluid, blood and fetal tissues. Tissue cytokine mRNA will be quantitated by real-time PCR. Fetal lung damage will be assessed by histopathologic and immunohistochemical methods and by lung morphometry. The gastrointestinal tract, meninges and brain will be examined for inflammation. Death of oligodendrocyte progenitors and other cell types in cerebral white matter will be evaluated by immunohistochemical methods and assays for apoptosis. The work proposed is unique in its use of combined interventional strategies in a well established nonhuman primate model of intrauterine infection. The results should illuminate the causal role of ureaplasma in prematurity and lead to advances in clinical management.