Mechanisms of Inflammation in Gestational Membranes

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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.