Low birth weight, uterine infection, and nitric oxide

泌尿生殖道感染和宿主因素往往与低出生体重有关，特别是在少数族裔。 种群大多数病原体，包括大肠杆菌，都会形成独特的毒力机制来定植和 侵入泌尿生殖道的细菌粘附素，如E-COL的DR菌毛与宿主组织受体相互作用 允许上行性感染和相关并发症一氧化氮(NO)，一种用途广泛的气体分子 据报道，包括调节感染和免疫在内的功能由子宫胎盘产生 组织这个项目的目标是评估NO是否通过调节调节子宫感染的严重程度 细菌侵入细胞我们假设没有系统调节子宫胎盘细菌受体， 腐烂加速因子(DAF)和细菌入侵。我们认为这种新的机制可以 在感染严重程度和低出生体重等围产期发病率方面发挥作用这些假设将 通过追求三个特定目标进行测试特定目标1将确定是否没有抑制DR E线圈附着- 上皮细胞的迁移和内化以及这是否通过抑制DAF的表达而发生 子目标1.1将表征子宫上皮细胞系中的NO产生，NO合成酶(NOS)酶， Ishikawa，RL-95和HEC-1细胞子目标1.2将检验这一假设，如果在这些细胞中操纵NO合成 细胞，将改变DR E线圈的附着和内化子目标1.3将测试上皮细胞 细胞DAF蛋白和信使核糖核酸的含量不受系统特异性目标2的调节。 大鼠子宫DAF含量的变化和NO合成的改变将改变感染的严重程度。 实验性宫内感染中的血管系统次级目标2.1将检验以下假设：DR*E线圈或B组 子宫胎盘组织中链球菌(GBS)感染减少，NO合成增加， 随着NO合成的抑制而增加子目标2.2将检验DAF含量变化的假设 子宫胎盘和血管组织与一氧化氮合成的变化有关特异靶3将检查 抑制NO合成和实验性宫内感染DR E或GBS可导致胎儿生长 在老鼠身上进行限制，如果是这样，是否没有捐赠者可以逆转胎儿生长限制子目标3.1将测试 假设抑制NO合成与宫内DR E线圈或GBS感染具有协同作用 对胎儿和胎盘生长的有害影响子目标3.2将测试没有捐赠者可以的假设 逆转子宫胎盘和血管组织及胎儿生长受限中DAF表达的增加

Urogenital infections and host factors are often associated with low birth weight, especially in minority populations Most pathogens, including Escherichia coil, develop unique virulence mechanisms to colonize and invade the urogenital tract Bacterial adhesins such as Dr fimbriae of E col interact with host tissue receptors allowing ascending infection and associated complications Nitric oxide (NO), a gaseous molecule with versatile functions including the modulation of infection and immunity, is reported to be produced by uteroplacental tissues The goal of this project is to assess if NO modulates severity of uterine infection through the regulation of bacterial invasion into cells We hypothesize that NO system regulates the uteroplacental bacterial receptor, decay accelerating factor (DAF) and therefore bacterial invasion We propose that this novel mechanism could play a role in severity of infection and perinatal morbidities such as low birth weight These hypotheses will be tested by pursuing three specific aims Specific Aim 1 will determine whether NO inhibits Dr+ E coil attach- ment and internalization into epithelial cells and whether this occurs through suppression of DAF expression Sub-aim 1.1 will characterize NO production, NO synthase (NOS) enzymes in uterine epithelial cell lines, Ishikawa, RL-95 and HEC-1 cells Sub-aim 1.2 will test the hypothesis if manipulation of NO synthesis in these cells, will alter Dr +E coil attachment and internalization Sub-aim 1.3 will test the hypothesis that the epithelial cell DAF protein and mRNA contents are regulated by NO system Specific Aim 2 will establish that modula- tion of NO synthesis in rats will alter severity of infection through the changes in DAF content of the uterus and vasculature in experimental intrauterine infection Sub-aim 2.1 will test the hypothesis that Dr* E coil or group B streptococcus (GBS) infection in uteroplacental tissues is reduced with increases in NO synthesis and is increased with the inhibition of NO synthesis Sub-aim 2.2 will test the hypothesis that changes in DAF content of uteroplacental and vascular tissues are related to chang+es in NO synthesis Specific Aim 3 will examine if inhibition of NO synthesis and experimental intrauterine Dr E coil or GBS infection results in fetal growth restriction in rats, and if so, whether NO donor can reverse the fetal growth restriction Sub-aim 3.1 will test the hypothesis that inhibition of NO synthesis combined with intrauterine Dr+E coil or GBS infection has synergistic detrimental effects on fetal and placental growth Sub aim 3.2 will test the hypothesis that NO donor can reverse the increases in DAF expression in uteroplacental and vascular tissues and in fetal growth restriction