Mechanisms of Inflammation in Gestational Membranes

描述（由申请人提供）：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很重要的，因为炎症相关的细胞因子和前列腺素的释放在早产和其他不良分娩结局之间有很强的联系。本研究解决的关键知识空白包括：1)环境污染物等非感染性刺激引发妊娠膜炎症，2)传染性和非感染性刺激激活MAPK通路，以及3)MAPK和NFkB通路的正反馈导致细胞因子和前列腺素产生的串扰和扩增。总的假设是，传染性和非传染性因子通过激活和正反馈MAPK和NFkB信号转导途径刺激促炎细胞因子和前列腺素的释放增加。这一假设将通过暴露于细菌毒素脂多糖（LPS）作为模型感染性刺激和环境污染物多溴联苯醚（PBDEs）和p，p'-DDE作为模型非感染性刺激的人类妊娠膜细胞和组织外植体培养来验证。具体目的是：1)确定pbde刺激的促炎细胞因子和前列腺素释放在人胎膜中的细胞靶点；2)确定多溴二苯醚是否在相关浓度下刺激妊娠组织中促炎细胞因子的释放；3)描述NF-:B和MAPK通路在感染因子和非感染因子刺激下人胎膜细胞因子和前列腺素合成中的作用；4)确定前列腺素和细胞因子是否通过NF-:B和MAPK通路以正反馈的方式相互作用，以增加妊娠膜中前列腺素的产生，以响应感染性和非感染性促炎刺激。这项研究的结果将增加我们对妊娠膜炎症原因的理解，因此，可能有助于通过加强预测和预防早产风险和其他相关不良分娩结局的策略来改善妊娠结局。减少早产是《2010年健康人口》的目标。公共卫生相关性：关于污染物对早产的影响的知识很少，然而对污染物对妊娠风险的流行病学研究是困难的、昂贵的和耗时的。鉴于孕妇可能接触到成千上万种化学品，需要制定一项策略来选择接触何种化学品进行流行病学分析。以多溴二苯醚和二苯二苯醚为模型毒物考察生物学合理性，为进一步研究污染物的选择提供了合理的途径。此外，这项研究的结果可能会增加对妊娠膜炎症原因的理解，因此，可能有助于通过加强预测和预防早产风险的策略来改善妊娠结局。

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.