Mechanisms of Inflammation in Gestational Membranes

描述（由申请方提供）：本研究的总体目标是了解MAPK和NFkB通路在胎盘外妊娠膜炎症病因学中的作用。了解妊娠膜炎症的病因是重要的，因为早产和其他不良出生结局中炎症相关的细胞因子和肾上腺素释放之间存在密切联系。本研究中解决的关键知识差距是：1）非感染性刺激（如环境污染物）引发妊娠膜炎症，2）感染性和非感染性刺激激活MAPK途径，3）MAPK和NFkB途径正反馈导致细胞因子和前列腺素产生的串扰和放大。总体假设是感染性和非感染性因子通过MAPK和NFkB信号转导途径的激活和正反馈刺激促炎细胞因子和胰高血糖素的释放增加。将使用暴露于细菌毒素脂多糖（LPS）作为模型感染刺激物的人妊娠膜细胞和组织外植体培养物以及环境污染物多溴联苯醚（PBDEs）和p，p '-DDE作为模型非感染刺激物来测试这一假设。具体目标是：1）确定多溴二苯醚刺激促炎细胞因子和前列腺素释放的人类妊娠膜中的细胞靶点; 2）确定多溴二苯醚在相关浓度下是否刺激妊娠组织中促炎细胞因子的释放; 3）描述NF-：B和MAPK途径在感染性和非感染性物质刺激后人类妊娠膜中细胞因子和前列腺素合成中的作用;和4）确定在感染性和非感染性促炎性刺激的反应中，洋地黄素和细胞因子是否通过NF-：B和MAPK途径以正反馈方式相互作用，以放大妊娠膜中洋地黄素的产生。这项研究的结果将增加我们对妊娠膜炎症原因的了解，因此，通过加强预测和预防早产风险和其他相关不良出生结局的策略，可能有助于改善妊娠结局。减少早产是《2010年健康人》的一个目标。公共卫生相关性：关于污染物对早产的贡献的知识很少，但污染物对妊娠风险的流行病学研究是困难、昂贵和耗时的。鉴于孕妇可能接触的化学品数以千计，需要制定一项战略，以选择用于流行病学分析的接触。以PBDEs和DDE为模型毒物研究生物可降解性，为进一步研究污染物的选择提供了一种合理的方法。此外，这项研究的结果可能会增加对妊娠膜炎症原因的了解，因此，通过加强预测和预防早产风险的策略，可能有助于改善妊娠结局。

DESCRIPTION (provided by applicant): The overall objective of this research is to understand the contribution of the MAPK and NFkB pathways in the etiology of inflammation of extra-placental gestational membranes. Understanding the etiology of inflammation in gestational membranes is important because of the strong link between inflammation-associated release of cytokines and prostaglandins in preterm birth and other adverse birth outcomes. The critical knowledge gaps addressed in this research are: 1) initiation of inflammation in gestational membranes by noninfectious stimuli such as environmental pollutants, 2) activation of the MAPK pathway by infectious and noninfectious stimuli, and 3) cross-talk and amplification of cytokine and prostaglandin production by positive feedback on the MAPK and NFkB pathways. The overarching hypothesis is that infectious and noninfectious agents stimulate increased release of pro- inflammatory cytokines and prostaglandins through activation and positive feedback of the MAPK and NFkB signal transduction pathways. This hypothesis will be tested using human gestational membrane cell and tissue explant cultures exposed to the bacterial toxin lipopolysaccharide (LPS) as a model infectious stimulus and the environmental pollutants polybrominated diphenyl ethers (PBDEs) and p,p'-DDE as model noninfectious stimuli. The Specific Aims are to: 1) identify the cell targets in human gestational membranes for PBDE-stimulated release of proinflammatory cytokines and prostaglandins; 2) determine whether PBDEs stimulate release of pro- inflammatory cytokines from gestational tissues at relevant concentrations; 3) delineate the roles of the NF-:B and MAPK pathways in cytokine and prostaglandin synthesis in human gestational membranes following stimulation with infectious and noninfectious agents; and 4) determine whether prostaglandins and cytokines interact in a positive feedback manner through the NF-:B and MAPK pathways to amplify production of prostaglandins in gestational membranes in response to infectious and noninfectious pro-inflammatory stimuli. Results from this research will increase our understanding of the causes of inflammation in gestational membranes and, as such, may contribute to improved pregnancy outcomes through enhanced strategies for prediction and prevention of risks for preterm birth and other associated adverse birth outcomes. Reducing preterm births is a Health People 2010 objective. PUBLIC HEALTH RELEVANCE: Knowledge of pollutant contributions to preterm birth is scarce, yet epidemiologic study of pollutant risks to pregnancy is difficult, expensive and time-consuming. Given the thousands of chemicals to which pregnant women may be exposed, a strategy is required for selection of exposures for epidemiologic analysis. By using PBDEs and DDE as model toxicants to investigate biologic plausibility, the proposed experiments may provide a rational approach for selection of pollutants for further study. Moreover, the results from this research may increase understanding of the causes of inflammation in gestational membranes and, as such, may contribute to improved pregnancy outcomes through enhanced strategies for prediction and prevention of risks for preterm birth.