Daneshmand Sean S, Chmait Ramen H, Moore Thomas R, Bogic Ljubica
Division of Perinatal Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla 92093-0802, USA.
Am J Obstet Gynecol. 2002 Nov;187(5):1131-6. doi: 10.1067/mob.2002.127145.
We hypothesize that vascular endothelial growth factor, a known angiogenic and permeability factor that is locally expressed in fetal membranes and decidua, may be the primary regulator in the pathway that eventually leads to preterm premature rupture of membranes. Our objective was to test the hypothesis that, both in the presence and in the absence of histologic chorioamnionitis, there is an increased expression of the vascular endothelial growth factor gene and its receptor Flt-1 in the human fetal membranes.
Membranes were sampled from a region that was distinct as the rupture site from three groups of patients with preterm premature rupture of membranes. Groups 1 and 2 differed only in the length of the latency period from rupture of the membranes to delivery. Group 3 included preterm patients with intact membranes, who acted as control subjects. All patients who were selected for the study lacked clinical signs of chorioamnionitis and were delivered by cesarean delivery. Tissue samples were analyzed for interleukin-6 gene expression by Northern blot analysis and for the presence of interleukin-6 protein by immunocytochemistry. The expression of vascular endothelial growth factor and Flt-1 genes was analyzed by in situ hybridization.
All tissue samples from group 1 and five tissue samples from group 2 (designated as group 2A) showed expression of the interleukin-6 gene and the presence of interleukin-6 protein in the fetal membranes (P <.001) and were therefore identified as inflamed. Five tissue samples from the patients in group 2 (designated as group 2B) and all control tissue samples showed neither evidence of interleukin-6 gene expression nor the presence of its protein and therefore were identified as not inflamed. Vascular endothelial growth factor and Flt-1 gene expression were increased significantly in the fetal membrane and decidua samples that were obtained from the noninflamed tissues from group 2B (P <.005) yet showed further enhancement in expression in the inflamed tissues.
The expression patterns of vascular endothelial growth factor and Flt-1 genes are indicative of a molecular pathologic condition of fetal membranes, regardless of their inflammatory status, which suggests their role as a primary regulator of preterm premature rupture of membranes.
我们推测血管内皮生长因子，一种已知的血管生成和通透性因子，在胎膜和蜕膜中局部表达，可能是最终导致胎膜早破途径中的主要调节因子。我们的目的是检验这一假设：无论是否存在组织学绒毛膜羊膜炎，人胎膜中血管内皮生长因子基因及其受体Flt-1的表达均增加。
从三组胎膜早破患者的胎膜破裂部位不同的区域采集胎膜样本。第1组和第2组仅在胎膜破裂至分娩的潜伏期长短上有所不同。第3组包括胎膜完整的早产患者，作为对照。所有入选本研究的患者均无绒毛膜羊膜炎的临床体征，且均行剖宫产分娩。通过Northern印迹分析检测组织样本中白细胞介素-6基因的表达，并通过免疫细胞化学检测白细胞介素-6蛋白的存在情况。通过原位杂交分析血管内皮生长因子和Flt-1基因的表达。
第1组的所有组织样本和第2组的5个组织样本（称为2A组）在胎膜中均显示白细胞介素-6基因的表达及白细胞介素-6蛋白的存在（P<.001），因此被确定为有炎症。第2组患者的5个组织样本（称为2B组）和所有对照组织样本均未显示白细胞介素-6基因表达的证据及其蛋白的存在，因此被确定为无炎症。从2B组非炎症组织获得的胎膜和蜕膜样本中，血管内皮生长因子和Flt-1基因表达显著增加（P<.005），但在炎症组织中表达进一步增强。
血管内皮生长因子和Flt-1基因的表达模式表明胎膜存在分子病理状况，无论其炎症状态如何，这提示它们在胎膜早破中作为主要调节因子的作用。
