PLACENTAL CYTOKINES AND PATHOGENESIS OF PREECLAMPSIA

滋养层浸润不足和 螺旋动脉引发局灶性胎盘缺血和缺氧 先兆子痫 胎盘缺氧与 胎盘循环产生“有毒”因子 据称通过破坏血管而导致母体疾病 内皮功能 滋养层细胞和其他胎盘细胞 通常会产生多种细胞因子，这些细胞因子可能 对血管内皮有害。 我们最近发现 滋养层和其他胎盘细胞也表达 促红细胞生成素（EPO），这是原型分子， 缺氧的转录调控。 这一发现表明， 和逻辑的方法来缩小搜索“有毒” 在先兆子痫期间由缺氧在胎盘中产生的因子， 多年来一直难以捉摸。 也就是说， 与低氧反应增强子元件同源的DNA序列 编码各种细胞因子的基因中EPO的表达可以提供 胎盘缺氧和这些物质的过度产生之间可能存在联系 潜在的有害因素。 的确，我们的 初步实验表明，缺氧刺激产生 胎盘绒毛外植体和血浆中的TNF-α和IL-1 β TNF-α在先兆子痫中升高。 这一总体目标 一项拨款提案是调查细胞因子是否在 胎盘对缺氧的反应导致 血浆水平，因此，内皮细胞活化和功能障碍， 先兆子痫 尽管很有说服力，但证据表明 内皮激活和功能障碍的疾病主要是 间接证据 因此，另一个目标是提供直接的 通过研究内皮细胞的表达， 细胞活化产物（与细胞因子 刺激）对皮肤活组织检查中血管内皮的作用， 以及腹壁下动脉和静脉的分支。 五个假设和具体目标，列在 研究计划，测试发病机制的各个方面， 先兆子痫，如以下一般图式中所提出的。 值得注意的是， 疾病的病因可能与缺乏 滋养层侵入未被该提议所解决。 螺旋动脉滋养层浸润不足-->局灶性 胎盘缺氧AIM 4> 胎盘细胞因子AIM 2的过度产生>升高的血浆 细胞因子 目的1和3 >内皮激活和功能障碍 目标5>疾病表现

Inadequate trophoblast invasion and physiologic remodelling of spiral arteries initiate focal placental ischemia and hypoxia in preeclampsia. Placental hypoxia has been implicated in the production of "toxic" factor(s) by the placenta which circulate causing maternal disease allegedly by compromising vascular endothelial function. Trophoblasts and other placental cells normally produce a variety of cytokines, which are potentially deleterious to the vascular endothelium. We recently discovered that trophoblasts and other placental cells also express erythropoietin (EPO), which is the prototype molecule for transcriptional regulation by hypoxia. This finding suggests a new and logical approach to narrowing the search for the "toxic" factor(s) produced in the placenta by hypoxia during preeclampsia, that have remained elusive for years. That is, identification of DNA sequences homologous to the hypoxic responsive-enhancer element of EPO within the genes encoding various cytokines may provide a possible link between placental hypoxia and overproduction of these potentially deleterious factors in preeclampsia. Indeed, our preliminary experiments show that hypoxia stimulates production of TNF-alpha and IL-1beta by placental villous explants, and plasma TNF-alpha is elevated in preeclampsia. An overall goal of this grant proposal is to investigate whether cytokines are overproduced by the placenta in response to hypoxia contributing to increased plasma levels, and thus, endothelial activation and dysfunction in preeclampsia. Although compelling, the evidence suggesting endothelial activation and dysfunction in the disease is mainly circumstantial. Therefore, another goal is to provide direct evidence for endothelial activation by investigating the expression of products of cellular activation (consistent with cytokine stimulation) on the endothelium of blood vessels in skin biopsies, as well as in branches of inferior epigastric arteries and veins. Five Hypotheses and Specific Aims, listed under Specific Aims in the Research Plan, test various aspects of the pathogenesis of preeclampsia as proposed in the following general schema. Of note, the etiology of the disease presumably related to deficient trophoblast invasion is not addressed by this proposal. DEFICIENT TROPHOBLAST INVASION OF SPIRAL ARTERIES------>FOCAL PLACENTAL HYPOXIA AIM4> OVERPRODUCTION OF PLACENTAL CYTOKINES AIM 2 >ELEVATED PLASMA CYTOKINES AIMS 1 & 3 >ENDOTHELIAL ACTIVATION AND DYSFUNCTION AIM5 >DISEASE MANIFESTATIONS