Thrombin-Stimulated Intrauterine Signaling Pathway

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DESCRIPTION (provided by applicant): Preterm delivery, which complicates 8-10% of pregnancies in the United States, results in significant neonatal and pediatric morbidity, and is responsible for about 75% of the neonatal mortality. The mechanisms underlying the onset of preterm labor are unclear; however, studies to date suggest that preterm delivery is often associated with genital tract infection, as suggested by elevated proinflammatory cytokines (e.g. IL2, ILa, TNF-a, and IFN-g). Although it has been shown that these cytokines lead to increased prostaglandin production by intrauterine tissues, it is unclear whether this is the only mechanism by which these pro-inflammatory cytokines lead to the stimulation of preterm contractions. The research described in this RO1 application will test the hypothesis: endotoxin (LPS) stimulates increased proinflammatory cytokines, especially IL-2, TNF-a and IFN-g resulting in activation of the "thrombin stimulated intrauterine signaling pathway"; i.e. enhanced phospholipid scramblase (PLS), tissue prothrombinase (Fgl2), prothrombin and thrombin receptor (PAR1) expression and activation leading to preterm contractions and delivery. Our preliminary studies have confirmed the molecular expression of all of the components of this pathway within the near term rat uterus. Using the LPS-induced preterm delivery model in the timed-pregnant rat, we will complete the following specific aims: 1) determine if Fgl2 expression and activation are increased in the preterm rat uterus, leading to prothrombinase activity, 2) determine if phospholipid scramblase expression and functional activity increase in the preterm rat uterus, leading to enhanced Fgl2 activity, 3) determine if increased intrauterine prothrombin expression occurs, leading to enhanced thrombin generation, 4) determine if uterine PAR-1 expression and activation are increased, leading to myometrial contractions, decidual necrosis, and intrauterine bleeding, and 5) test the hypothesis that the above phenomena occur in parallel and contribute to the role of prostaglandins during the events leading to LPS-stimulated preterm labor and delivery in the rat. These studies are anticipated to significantly improve our understanding of the mechanisms underlying preterm labor in the presence of intrauterine infection.