Project 2 ROLE OF THE FETUS IN THE INFLAMMATORY RESPONSE AND COMPROMISE OF

我们假设，在女性和其他哺乳动物中，子宫静止是通过增加孕酮受体（PR）转录活性来维持的，而自然分娩是由一系列协同的生化事件启动或促进的，这些生化事件激活了炎症反应途径，降低了辅激活因子水平，并对PR功能产生了负面影响。在最近的研究中，我们观察到PR共激活因子、creb结合蛋白（CBP）和类固醇受体共激活因子（SRC）家族成员，以及分娩妇女子宫肌层和足月妊娠小鼠子宫组织中组蛋白乙酰化的显著下降。

We postulate that in women, as well as other mammalian species, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, and that spontaneous labor is initiated or facilitated by a concerted series of biochemical events that activate inflammatory response pathways, reduce coactivator levels and negatively impact PR function. In recent studies, we observed a marked decline in the PR coactivators, CREB-binding protein (CBP) and members of the steroid receptor coactivator (SRC) family, and in histone acetylation in myometrium of women in labor and in uterine tissues of pregnant mice at term. CBP and several SRC family members have histone acetylase activity, which maintains an open chromatin structure. Pregnant mice injected with a histone deacetylase inhibitor near term manifested increased histone acetytation in the uterus and delayed parturition, suggesting the functional importance of the decline in coactivators in the initiation of parturition. We also obtained intriguing data to suggest that the major lung surfactant protein, SP-A, a C-type lectin involved in innate immune response, that is developmentally regulated in fetal lung and secreted into amniotic fluid near term, signals the initiation of labor. SP-A activates amniotic fluid macrophages to express nuclear factor kappaB (NF-kappaB) and interleukin-1beta (IL-1beta). These macrophages, which are of fetal origin, migrate to the pregnant uterus leading to an inflammatory response and increased uterine NF-kappaB activity. We suggest that the increase in NF-kappaB within the maternal uterus both directly increases expression of genes that promote uterine contractility and negatively impacts the capacity of the PR to maintain uterine quiescence, contributing to the onset of labor. Based on these findings, the following research objectives are proposed: (1) to further define the role of SP-A and of the related surfactant protein, SP-D, in the initiation of labor;, (2) to characterize the receptors and signaling mechanisms whereby SP-A at term activates macrophages in amniotic fluid, resulting in activation of NF-kappaB in the maternal uterus; (3) to determine the cellular and molecular mechanism(s) for the decline in expression of coactivators within the myometrium at term, and; (4) to decipher the molecular mechanisms whereby progesterone and NF-kappaB regulate target genes that control quiescence/contractility of the myometrium. We believe that this research will provide important insight into the molecular mechanisms that mediate the decline in coactivators and the role played by maturation of the fetal lung and secretion of pulmonary surfactant in activation of inflammatory response pathways within the pregnant uterus that culminate in parturition.