EXPERIMENTAL MODEL FOR CHORIOAMNIONITIS AND PREMATURITY

绒毛膜羊膜炎和早产的实验模型

• 批准号: 2673171
• 负责人: MICHAEL G GRAVETT
• 金额: $ 19.85万
• 依托单位: OREGON REGIONAL PRIMATE RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2673171
• 关键词: Enterococcus; Macaca mulatta; amniotic fluid; antibiotics; combination therapy; cytokine; drug screening /evaluation; immunosuppressive; interleukin 1; interleukin 10; lipoxygenase; model design /development; physical chemical interaction; pregnancy infection; premature labor; prostaglandins; steroid hormone

Prematurity is the leading cause of neonatal morbidity and mortality in the United States. The 8% of neonates born prematurely account for 70% of all perinatal deaths hot attributed to congenital malformations. A growing body of evidence suggests that intrauterine infections are an important, and potentially treatable cause of prematurity. However, the mechanisms by which infection leads to prematurity remain speculative and treatment strategies untested largely because humans cannot be longitudinally studied following infection. We propose to use chronically instrumented pregnant rhesus monkeys (n: 36) at 120-130 days gestation with experimental intrauterine infection, as previously described (Gravett et al, Am J Obstet & Gynecol; 171:1660-1667,1994) to study the temporal and quantitative relationships among infection, cytokines, prostaglandins, lipoxygenase derivatives, steroid hormones, cytokine antagonists, and preterm labor in order to develop effective interventional strategies. After postoperative stabilization in a tether, we will (1) infuse proinflammatory cytokine IL-1beta into the amniotic cavity through previously placed indwelling catheters in the absence of infection (n=16); (2) inoculate Group 8 streptococci (GBS) into the amniotic fluid to establish intrauterine infection and preterm labor (n=20). 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, complement and heat-shock proteins, and for microbial studies. Prior to infusion of IL-1beta in the absence of infection, potent inhibitors of proinflammatory cytokine production (dexamethasone, interleukin-10) or prostaglandin production (indomethacin) will be used to ascertain the most effective intervention to down-regulate the cytokine/prostaglandin cascade and associated uterine activity. The immunosuppressants or prostaglandin synthase inhibitor will be similarly studied in combination with antibiotics in the setting of experimental intrauterine infection with GBS. Samples of the decidua, placenta, and fetal tissue will be obtained at cesarean section for microbiologic, histopathologic, and studies for cytokine mRNA localization and quantitation. The fetus is pre-viable and will be euthanized. 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.

早产是新生儿发病和死亡的主要原因 在美国8%的早产新生儿， 70%的围产期死亡归因于先天畸形。 越来越多的证据表明，子宫内感染是 一个重要的，潜在的可治疗的早产原因。然而，在这方面， 感染导致早产的机制仍然存在， 投机和治疗策略未经测试，主要是因为人类 不能在感染后进行纵向研究。我们建议使用 慢性仪器妊娠恒河猴（n：36）在120-130 与先前一样，妊娠30天，伴有实验性宫内感染 描述（Gravett等，Am J Obstet&Gynecol; 171：1660- 1667，1994） 为了研究感染之间的时间和数量关系， 细胞因子，洋地黄素，脂氧合酶衍生物，类固醇激素， 细胞因子拮抗剂和早产，以开发有效的 干预策略。术后稳定后， 系链，我们将（1）将促炎细胞因子IL-1 β注入 羊膜腔通过先前放置的留置导管在 无感染（n=16）;（2）第8组链球菌（GBS） 进入羊水中以确定宫内感染和早产 分娩（n=20）。将持续监测子宫收缩力， 定期采集羊水、母体和胎儿血液样本（1-4 cc）用于测定类二十烷酸，类固醇激素， 细胞因子、补体和热休克蛋白，以及微生物 问题研究在没有感染的情况下输注IL-1 β之前， 促炎细胞因子产生的有效抑制剂 （地塞米松、白细胞介素-10）或前列腺素产生 （吲哚美辛）将用于确定最有效的 下调细胞因子/前列腺素级联的干预， 相关的子宫活动。免疫抑制剂或者前列腺素 合成酶抑制剂将类似地与 抗生素在实验性宫内感染中的应用 GBS。将采集蜕膜、胎盘和胎儿组织样本， 在剖宫产时获得用于微生物学、组织病理学和 细胞因子mRNA定位和定量研究。胎儿 预存活并将被安乐死。产后，母亲会 用适当的抗生素治疗，以消除GBS从 生殖道，并返回到殖民地。这些研究将阐明 感染相关性早产的病理生理学和意愿 提出有效的干预策略。