PLACENTAL CYTOKINES AND PATHOGENESIS OF PREECLAMPSIA

滋养层侵袭不足与胎盘生理性重构 螺旋动脉致胎盘局灶性缺血缺氧 先兆子痫。胎盘缺氧与胎盘发育迟缓 循环胎盘产生“有毒”因子(S) 据称通过损害血管而导致产妇疾病 内皮功能。滋养层细胞和其他胎盘细胞 通常会产生各种细胞因子，这些细胞因子可能会 对血管内皮细胞有害。我们最近发现 滋养层细胞和其他胎盘细胞也表达 促红细胞生成素(EPO)，这是 低氧对转录的调节。这一发现提出了一种新的 和合乎逻辑的方法来缩小“有毒”的搜索范围 先兆子痫胎盘缺氧产生的因子(S) 这些问题多年来一直难以捉摸。也就是说，识别 与缺氧反应增强元件同源的DNA序列 在编码各种细胞因子的基因中的EPO可以提供 胎盘缺氧与这些物质的过度产生之间可能存在联系 先兆子痫的潜在有害因素。的确，我们的 初步实验表明，低氧刺激产生 胎盘绒毛组织和血浆中的肿瘤坏死因子-α和白介素1-β 先兆子痫患者血清肿瘤坏死因子-α水平升高。这方面的总体目标是 格兰特的提议是调查细胞因子是否过度产生 由胎盘对缺氧的反应增加 血浆水平，从而，内皮细胞激活和功能障碍 先兆子痫。尽管令人信服，但证据表明 血管内皮细胞活化和功能障碍在本病中主要是 间接证据。因此，另一个目标是提供直接的 通过研究血管内皮细胞的表达证明内皮细胞的激活 细胞活化产物(与细胞因子一致 刺激)对皮肤活检中的血管内皮细胞， 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，测试各方面的发病机制 先兆子痫，如下图所示。值得注意的是， 该病的病因学推测与虚证有关 滋养层细胞的侵袭不是这项提议的内容。 滋养层细胞缺乏对螺旋动脉的侵袭-&gt；病灶 胎盘缺氧AIM4和GT； 胎盘细胞因子的过度产生&血浆升高 细胞因子 AIMS 1和3&gt；内皮细胞激活和功能障碍 AIM5&GT；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