Role of the fetus in the inflammatory response and compromise of progesterone

胎儿在​​炎症反应和黄体酮受损中的作用

• 批准号: 7721065
• 负责人: CAROLE R MENDELSON
• 金额: $ 23.53万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7721065
• 关键词: Alveolar Macrophages; Amniotic Fluid; Animals; Antibodies; Binding; Biochemical; Biological Assay; Birth; C-Type Lectins; CREB-binding protein; Cells; Chromatin Structure; Complement Factor B; Cultured Cells; DNA Binding; Data; Disruption; Electrophoretic Mobility Shift Assay; Event; Family; Family member; Fetal Lung; Fetus; Gel; Gene Activation; Gene Expression; Gene Targeting; Genes; Goals; Growth; Histone Acetylation; Histone Deacetylase Inhibitor; Histones; Human; Immune response; Inflammatory Response; Inflammatory Response Pathway; Injection of therapeutic agent; Labor Onset; Lung; Macrophage Activation; Mediating; Messenger RNA; Molecular; Mus; Myometrial; Nuclear; Patient currently pregnant; Pregnancy; Pregnant Uterus; Production; Progesterone; Progesterone Receptors; Protein Overexpression; Proteins; Pulmonary Surfactant-Associated Protein D; Pulmonary Surfactant-Associated Proteins; Pulmonary Surfactants; Receptor Inhibition; Receptor Signaling; Regulation; Research; Response Elements; Role; Role playing therapy; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Steroid Receptors; TLR2 gene; TLR4 gene; Time; Tissues; Toll-Like Receptor 2; Toll-like receptors; Transfection; Transgenic Mice; Trichostatin A; Uterus; Woman; base; chromatin immunoprecipitation; cytokine; day; fetal; fusion gene; gene repression; histone acetyltransferase; human CREBBP protein; human IRAK1 protein; inhibitor/antagonist; insight; macrophage; member; migration; mouse model; myometrium; nuclear receptor coactivator 1; progesterone receptor B; promoter; receptor; receptor expression; receptor function; surfactant; uterine contractility

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 KB (NF-KB) and intedeukin-ll3 (IL-113). These macrophages, which are of fetal origin, migrate to the pregnant uterus leading to an inflammatory response and increased uterine NF-_:B activity. We suggest that the increase in NF-KB 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-_B 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-KB regulate target genes that control quiescence/contractility of the myometdum. 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.

我们假设，在女性以及其他哺乳动物中，子宫静止是由以下因素维持的： 孕酮受体（PR）转录活性增加，自发分娩启动或促进 通过一系列协同的生物化学事件激活炎症反应途径， 辅激活因子水平和负面影响PR功能。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的组蛋白乙酰化。 CBP和几个SRC家族成员具有组蛋白乙酰化酶活性，其维持开放的染色质 结构近期注射组蛋白去乙酰化酶抑制剂的怀孕小鼠表现出增加 子宫中组蛋白乙酰化和延迟分娩，提示功能性重要性下降 在分娩开始的辅助激活因子中。我们还获得了有趣的数据，表明主要的肺 表面活性蛋白，SP-A，一种参与先天免疫应答的C型凝集素， 在胎儿肺中调节并分泌到羊水中，是分娩开始的信号。SP-A 激活羊水巨噬细胞以表达核因子KB（NF-κ B）和白介素-113（IL-113）。这些 巨噬细胞，其是胎儿来源的，迁移到妊娠子宫，导致炎症反应 增加子宫NF-_：B活性。我们认为母体子宫内NF-κ B的增加 直接增加促进子宫收缩的基因表达，并对子宫收缩能力产生负面影响。 PR维持子宫静止，有助于分娩的开始。根据这些发现， 提出了以下研究目标：（1）进一步明确SP-A及其相关表面活性剂的作用 蛋白质，SP-D，在劳动的启动;（2）表征受体和信号机制， 足月时SP-A激活羊水中的巨噬细胞，导致母体子宫中NF-_B的激活; (3)以确定细胞内共激活因子表达下降的细胞和分子机制， 子宫肌层在足月，和（4）破译的分子机制，孕酮和NF-κ B 调节控制子宫肌层静止/收缩的靶基因。我们相信这项研究 将提供重要的深入了解介导的分子机制，在共激活剂的下降， 胎肺成熟和肺表面活性物质分泌在炎症激活中的作用 在分娩时达到高潮的怀孕子宫内的反应途径。