Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, Connecticut, USA.
Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Reproduction. 2020 Jan;159(1):73-80. doi: 10.1530/REP-19-0422.
Pre-gestational diabetes is a risk factor for preeclampsia, a condition associated with inflammatory markers, a dysregulated angiogenic profile, and impaired placentation. Using an in vitro model, we previously reported that hyperglycemic levels of glucose induced a pro-inflammatory (IL-1β, IL-8, RANTES, GRO-α), anti-angiogenic (sFlt-1) and anti-migratory profile in a human trophoblast cell line. The IL-1β response to excess glucose was mediated by uric acid-induced activation of the NLRP3 inflammasome. Allopurinol is a xanthine oxidase inhibitor that inhibits uric acid and reactive oxygen species (ROS) production. Thus, we sought to test the effects of allopurinol on the IL-1β and other inflammatory, angiogenic and migratory responses that are triggered in the trophoblast by excess glucose. Under excess glucose conditions, allopurinol significantly inhibited trophoblast secretion of inflammatory IL-1β; caspase-1 activity; IL-8; RANTES; and GRO-α. Allopurinol also significantly inhibited excess glucose-induced trophoblast secretion of anti-angiogenic sFlt-1. The presence of IL1Ra significantly inhibited excess glucose-induced trophoblast IL-8 and GRO-α secretion but had no effect on RANTES or sFlt-1. Conversely, DPI, a ROS inhibitor, significantly inhibited excess glucose-induced trophoblast GRO-α and sFlt-1 secretion, but had no effect on IL-8 or RANTES. Together, our findings indicate that the xanthine oxidase inhibitor allopurinol inhibited excess glucose-induced trophoblast IL-1β secretion. Additionally, through its inhibition of both IL-1β and ROS production by the trophoblast, allopurinol reduced the additional pro-inflammatory and anti-angiogenic responses to excess glucose. Thus, allopurinol may be a candidate medication to prevent placental dysfunction and adverse pregnancy outcomes, such as preeclampsia, in pregnant women with diabetes.
孕前糖尿病是子痫前期的一个风险因素，子痫前期与炎症标志物、血管生成失调、胎盘功能障碍有关。我们之前在体外模型中报告，高血糖水平的葡萄糖会诱导人滋养细胞系产生促炎（IL-1β、IL-8、RANTES、GRO-α）、抗血管生成（sFlt-1）和抗迁移表型。IL-1β 对过量葡萄糖的反应是由尿酸诱导的 NLRP3 炎症小体激活介导的。别嘌醇是一种黄嘌呤氧化酶抑制剂，可抑制尿酸和活性氧（ROS）的产生。因此，我们试图测试别嘌醇对滋养细胞中由过量葡萄糖引发的 IL-1β 及其他炎症、血管生成和迁移反应的影响。在过量葡萄糖条件下，别嘌醇显著抑制滋养细胞分泌促炎细胞因子 IL-1β；半胱天冬酶-1 活性；IL-8；RANTES；和 GRO-α。别嘌醇还显著抑制过量葡萄糖诱导的滋养细胞分泌抗血管生成 sFlt-1。IL1Ra 的存在显著抑制了过量葡萄糖诱导的滋养细胞 IL-8 和 GRO-α 的分泌，但对 RANTES 或 sFlt-1 没有影响。相反，ROS 抑制剂 DPI 显著抑制了过量葡萄糖诱导的滋养细胞 GRO-α 和 sFlt-1 的分泌，但对 IL-8 或 RANTES 没有影响。总之，我们的研究结果表明，黄嘌呤氧化酶抑制剂别嘌醇抑制了过量葡萄糖诱导的滋养细胞 IL-1β 分泌。此外，通过抑制滋养细胞中 IL-1β 和 ROS 的产生，别嘌醇减少了对过量葡萄糖的额外促炎和抗血管生成反应。因此，别嘌醇可能是预防糖尿病孕妇胎盘功能障碍和不良妊娠结局（如子痫前期）的候选药物。
