Department of Pharmaceutical Sciences, St. John's University, 8000 Utopia Parkway, Jamaica, NY, 11439, USA; Women and Children's Research Laboratory, Winthrop University Hospital, 259 1st Street, Mineola, NY, 11501, USA.
Women and Children's Research Laboratory, Winthrop University Hospital, 259 1st Street, Mineola, NY, 11501, USA; Department of Pediatrics, Winthrop University Hospital, 259 1st Street, Mineola, NY, 11501, USA.
Toxicol Appl Pharmacol. 2015 Feb 1;282(3):275-84. doi: 10.1016/j.taap.2014.09.008. Epub 2014 Sep 16.
Preterm birth (PTB), defined as any delivery occurring prior to the completion of 37 weeks' gestation, currently accounts for 11-12% of all births in the United States. Maternal genito-urinary infections account for up to 40% of all PTBS and induce a pro-inflammatory state in the host. The potent vasoconstrictor Endothelin-1 (ET-1) is known to be upregulated in the setting of infection, and elicits its effect by binding to the ETA receptor. We have previously shown that antagonism of the ETA receptor with BQ-123 is capable of preventing LPS-induced PTB in mice. We hypothesize that the administration of BQ-123 post LPS exposure will dismantle a positive feedback loop observed with pro-inflammatory cytokines upstream of ET-1. On GD 15.5, pregnant C57BL/6 mice were injected with PBS, LPS, BQ-123, or LPS+BQ-123. Changes at both the level of transcription and translation were observed in uterus and placenta in the ET-1 axis and in pro- and anti-inflammatory cytokines over the course of 12h. We discovered that BQ-123, when administered 10h post LPS, is capable of increasing production of uterine and placental Interleukin-10, causing a shift away from the pro-inflammatory state. We also observed that antagonism of the ETA receptor decreased IL-1β and TNFα in the placenta while also decreasing transcription of ET-1 in the uterus. Our results reinforce the role of ET-1 at the maternal fetal interface and highlight the potential benefit of ETA receptor blockade via the suppression of ET-1, and induction of a Th2 cytokine dominant state.
早产（PTB），定义为发生在妊娠 37 周完成之前的任何分娩，目前占美国所有分娩的 11-12%。母体生殖道感染占所有 PTBS 的 40%，并在宿主中诱导炎症状态。已知在感染情况下内皮素-1（ET-1）被上调，并通过与 ETA 受体结合发挥其作用。我们之前已经表明，用 BQ-123 拮抗 ETA 受体能够防止 LPS 诱导的小鼠 PTB。我们假设，在 LPS 暴露后给予 BQ-123 将破坏 ET-1 上游的促炎细胞因子的正反馈环。在 GD 15.5 时，用 PBS、LPS、BQ-123 或 LPS+BQ-123 注射怀孕的 C57BL/6 小鼠。在 12 小时的过程中，在 ET-1 轴和促炎和抗炎细胞因子中观察到转录和翻译水平的变化。我们发现，在 LPS 后 10 小时给予 BQ-123 能够增加子宫和胎盘白细胞介素-10 的产生，导致从促炎状态转变。我们还观察到，ETA 受体的拮抗作用降低了胎盘中的 IL-1β 和 TNFα，同时也降低了子宫中 ET-1 的转录。我们的结果强化了 ET-1 在母体胎儿界面的作用，并强调了通过抑制 ET-1 和诱导 Th2 细胞因子优势状态来阻断 ETA 受体的潜在益处。
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