Experimental Model for Chorioamnionitis and Prematurity

绒毛膜羊膜炎和早产的实验模型

• 批准号: 6763049
• 负责人: MICHAEL G GRAVETT
• 金额: $ 27.83万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6763049
• 关键词: Macaca mulatta; Streptococcus agalactiae; antibiotics; antiinflammatory agents; brain disorder chemotherapy; cytokine; dexamethasone; disease /disorder model; embryo /fetus cell /tissue; embryo /fetus chemotherapy; embryo /fetus disorder; female; histopathology; immunocytochemistry; immunosuppressive; immunotherapy; indomethacin; interleukin 1; microorganism disease chemotherapy; neuropathology; newborn animals; nonhuman therapy evaluation; pregnancy disorder chemotherapy; pregnancy infection; premature labor; prostaglandin inhibitors

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.

早产是美国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且潜在可治疗的原因，并与新生儿脑白色病变和脑瘫的风险增加有关。 然而，感染导致早产和/或脑瘫的机制仍然是推测性的，治疗策略也没有经过测试，这主要是因为人类感染后不能进行纵向研究。 如前所述（Gravett等，Am J Obstet and Gynecol; 171：1660- 1667，1994），我们建议使用妊娠120-130天的慢性仪器化妊娠恒河猴，以研究感染、细胞因子、阿糖胞苷、类固醇激素、细胞因子拮抗剂、早产和新生儿脑白色物质损伤之间的时间和定量关系，以开发有效的干预策略。术后稳定后，我们将：（1）将B族链球菌（GBS）注入羊水中，以建立宫内感染和早产。将持续监测子宫收缩力，并定期采集羊水、母体和胎儿血液（1-4 cc）样本，用于类花生酸、类固醇激素、细胞因子、基质金属蛋白酶的测定和微生物研究;（2）使用具有或不具有促炎细胞因子产生的有效抑制剂的抗生素（地塞米松，IL-10）o前列腺素产生（吲哚美辛）以确定下调细胞因子/前列腺素级联和相关子宫活动的最有效干预;（3）在无感染的情况下，通过留置导管向羊膜腔内注入促炎细胞因子IL-1 β。在不存在感染的情况下输注IL-1 β之前，将使用特异性新型促炎细胞因子抑制剂（IL-1 ra和sTNF-R1 PEG）来鉴定其他潜在有用的免疫调节剂。 在剖宫产时采集蜕膜、胎膜、组织和脑样本，用于微生物学、组织病理学研究、细胞因子免疫组织化学、细胞因子和PGHS-2 mRNA的定位和定量。 将检查胎脑中与白色病变相关的细胞凋亡增加。 将通过流式细胞术评估羊水和气管抽吸物中的白细胞。产后，母亲将用适当的抗生素治疗以从生殖道根除GBS并返回到殖民地。 这些研究将阐明感染相关早产的病理生理学，并提出有效的干预策略。