Wang Xin, Athayde Neil, Trudinger Brian
Department of Obstetrics and Gynaecology, University of Sydney at Westmead Hospital, PO Box 533, Wentworthville, Westmead, NSW 2145, Australia.
Am J Obstet Gynecol. 2003 Nov;189(5):1445-51. doi: 10.1067/s0002-9378(03)00652-5.
Vascular disease in the umbilical placental circulation is associated with fetal growth restriction and adverse outcome. It may be identified antenatally by the study of umbilical artery Doppler flow velocity waveforms. The cause of this vascular disease is unknown. We have previously provided indirect evidence for endothelial cell activation and a proinflammatory cytokine response. Recently, a family of inhibitors of cytokine signaling has been identified, referred to as the suppressors of cytokine signaling (SOCS). Activation of SOCS occurs when cytokines are produced in stimulated cells. We tested the hypothesis that endothelial cell activation was present in umbilical placental vascular disease and was associated with production of proinflammatory cytokines and members of the family of SOCS.
Placentas were collected at delivery and microvascular endothelial cells were isolated. We studied 13 normal pregnancies and 10 with umbilical placental vascular disease identified by an abnormal umbilical artery Doppler study. Placental pieces were digested with collagenase and purified by adherence to Dynabeads coated with monoclonal antibody against CD31. The RNA was extracted from isolated endothelial cells. The messenger RNA expression of cytokine production (interleukin-6 and interleukin-8) and the members of SOCS family (CIS, SOCS1, SOCS2, and SOCS3) were assessed by use of semiquantitative reverse transcriptase-polymerase chain reaction.
In the microcirculation of the placenta, endothelial cell expression of interleukin-6 messenger RNA (2.50+/-0.60 vs 1.25+/-0.26) and interleukin-8 messenger RNA (2.83+/-0.55 vs 1.58+/-0.27) was up-regulated in umbilical placental vascular disease in comparison to normal pregnancy. The endothelial cell mRNA expression of SOCS2 (3.36+/-0.77 vs 1.76+/-0.29) and SOCS3 (2.77+/-0.60 vs 1.48+/-0.26) was enhanced in placental vascular disease. There was no significant difference in expression of CIS and SOCS1 in microvessel endothelial cells.
We have demonstrated that microvessel endothelium of the fetal placental vasculature produces both the proinflammatory cytokines (interleukin-6 and interleukin-8) and members of SOCS family (SOCS2 and SOCS3) in umbilical placental vascular disease. This cytokine production may play a key role in the interaction of endothelial cells of the placenta villi with neighboring cells. The up-regulation of SOCS2 and SOCS3 indicates these are the major negative regulators in umbilical placental microvessel endothelial cell activation pathways. By its occurrence, this also confirms the presence of a proinflammatory cytokine response.
脐胎盘循环中的血管疾病与胎儿生长受限及不良结局相关。可通过脐动脉多普勒血流速度波形研究在产前对其进行识别。这种血管疾病的病因尚不清楚。我们之前已提供了内皮细胞激活和促炎细胞因子反应的间接证据。最近，已鉴定出一族细胞因子信号抑制剂，称为细胞因子信号转导抑制因子（SOCS）。当细胞因子在受刺激细胞中产生时，SOCS会被激活。我们检验了以下假设：脐胎盘血管疾病中存在内皮细胞激活，且与促炎细胞因子及SOCS家族成员的产生有关。
分娩时收集胎盘并分离微血管内皮细胞。我们研究了13例正常妊娠和10例经脐动脉多普勒研究异常确诊为脐胎盘血管疾病的病例。胎盘组织用胶原酶消化，并通过黏附于包被有抗CD31单克隆抗体的磁珠进行纯化。从分离的内皮细胞中提取RNA。通过半定量逆转录聚合酶链反应评估细胞因子产生（白细胞介素-6和白细胞介素-8）及SOCS家族成员（CIS、SOCS1、SOCS2和SOCS3）的信使核糖核酸表达。
与正常妊娠相比，脐胎盘血管疾病中胎盘微循环中内皮细胞白细胞介素-6信使核糖核酸（2.50±0.60对1.25±0.26）和白细胞介素-8信使核糖核酸（2.83±0.55对1.58±0.27）的表达上调。胎盘血管疾病中SOCS2（3.36±0.77对1.76±0.29）和SOCS3（2.77±0.60对1.48±0.26）的内皮细胞信使核糖核酸表达增强。微血管内皮细胞中CIS和SOCS1的表达无显著差异。
我们已证明，在脐胎盘血管疾病中，胎儿胎盘血管系统的微血管内皮细胞可产生促炎细胞因子（白细胞介素-6和白细胞介素-8）及SOCS家族成员（SOCS2和SOCS3）。这种细胞因子的产生可能在胎盘绒毛内皮细胞与相邻细胞的相互作用中起关键作用。SOCS2和SOCS3的上调表明它们是脐胎盘微血管内皮细胞激活途径中的主要负调节因子。通过其发生情况，这也证实了促炎细胞因子反应的存在。
