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中的作用。了解妊娠膜炎症的病因很重要，因为早产中炎症相关的细胞因子和前列腺素的释放与其他不良分娩结果之间存在密切联系。本研究涉及的关键知识空白是：1)环境污染物等非感染性刺激引起胎膜炎症，2)感染性和非感染性刺激激活MAPK通路，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放大。最重要的假设是，感染性和非感染性因素通过激活和正反馈MAPK和NFkB信号转导通路，刺激促炎细胞因子和前列腺素的释放增加。这一假说将用暴露于细菌毒素脂多糖(LPS)的人胎膜细胞和组织外植体培养物作为模型感染性刺激，以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物。其具体目的是：1)确定PBDE刺激的人孕膜促炎细胞因子和前列腺素释放的细胞靶点；2)确定适当浓度的PBDEs是否刺激妊娠组织释放促炎细胞因子；3)阐明感染和非感染性因素刺激下，NF-：B和MAPK通路在人孕膜细胞因子和前列腺素合成中的作用；以及4)确定前列腺素和细胞因子是否通过NF-：B和MAPK途径相互作用，以放大孕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了解，因此，可能有助于通过改进预测和预防早产和其他相关不良分娩结果的风险的策略来改善妊娠结局。减少早产是2010年《健康人物》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，但对污染物对怀孕的风险进行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物质数以千计，因此需要有一种战略来选择暴露于何种化学物质以进行流行病学分析。通过使用多溴二苯醚和DDE作为模型毒物来考察生物可信度，本实验可能为进一步研究污染物的选择提供一种合理的途径。此外，这项研究的结果可能会增加对妊娠膜炎症原因的了解，并因此可能有助于通过加强预测和预防早产风险的战略来改善妊娠结局。

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.