Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada K7L3N6.
J Immunol. 2011 Feb 1;186(3):1799-808. doi: 10.4049/jimmunol.1002679. Epub 2010 Dec 27.
Abnormal maternal inflammation during pregnancy is associated with spontaneous pregnancy loss and intrauterine fetal growth restriction. However, the mechanisms responsible for these pregnancy outcomes are not well understood. In this study, we used a rat model to demonstrate that pregnancy loss resulting from aberrant maternal inflammation is closely linked to deficient placental perfusion. Administration of LPS to pregnant Wistar rats on gestational day 14.5, to induce maternal inflammation, caused fetal loss in a dose-dependent manner 3-4 h later, and surviving fetuses were significantly growth restricted. Pregnancy loss was associated with coagulopathy, structural abnormalities in the uteroplacental vasculature, decreased placental blood flow, and placental and fetal hypoxia within 3 h of LPS administration. This impairment in uteroplacental hemodynamics in LPS-treated rats was linked to increased uterine artery resistance and reduced spiral arteriole flow velocity. Pregnancy loss induced by LPS was prevented by maternal administration of the immunoregulatory cytokine IL-10 or by blocking TNF-α activity after treatment with etanercept (Enbrel). These results indicate that alterations in placental perfusion are responsible for fetal morbidities associated with aberrant maternal inflammation and support a rationale for investigating a potential use of immunomodulatory agents in the prevention of spontaneous pregnancy loss.
异常的母体炎症与自然流产和胎儿宫内生长受限有关。然而，导致这些妊娠结局的机制尚不清楚。在这项研究中，我们使用大鼠模型证明，由异常母体炎症引起的流产与胎盘灌注不足密切相关。在妊娠第 14.5 天给怀孕的 Wistar 大鼠注射 LPS 以诱导母体炎症，随后在 3-4 小时后以剂量依赖性方式导致胎儿丢失，幸存的胎儿明显生长受限。流产与凝血功能障碍、子宫胎盘血管结构异常、胎盘血流减少以及 LPS 给药后 3 小时内胎盘和胎儿缺氧有关。LPS 处理大鼠的子宫胎盘血液动力学受损与子宫动脉阻力增加和螺旋动脉血流速度降低有关。用免疫调节细胞因子 IL-10 进行母体给药或在用依那西普（Enbrel）治疗后阻断 TNF-α 活性可预防 LPS 引起的流产。这些结果表明，胎盘灌注的改变是导致异常母体炎症相关胎儿疾病的原因，并支持研究免疫调节剂在预防自然流产中的潜在用途的合理性。
