Aspirin and heparin effect on basal and antiphospholipid antibody modulation of trophoblast function.
Aspirin and heparin effect on basal and antiphospholipid antibody modulation of trophoblast function.
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DOI：
10.1097/aog.0b013e31823234ad
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发表时间：
2011-11
影响因子：
7.2
通讯作者：
Abrahams VM
中科院分区：
文献类型：
--
作者：
Han CS;Mulla MJ;Brosens JJ;Chamley LW;Paidas MJ;Lockwood CJ;Abrahams VM
低分子量 (LMW) 肝素，联合或不联合阿司匹林（乙酰水杨酸 [ASA]），用于预防妊娠期抗磷脂综合征的并发症。我们的目的是阐明低剂量 LMW 肝素和 ASA 对基础抗体和抗磷脂抗体诱导的滋养层功能调节的作用。在存在以下条件的情况下，使用或不使用抗磷脂抗体处理人妊娠早期滋养层细胞系 (HTR-8)：1) 无药物，2) 低剂量 LMW 肝素，3) 低剂量 ASA，或 4) 联合治疗。检测上清液中白介素 (IL)-6、IL-8、IL-1β、生长调节癌基因-α、血管内皮生长因子 (VEGF)、胎盘生长因子 (PlGF)、可溶性 FMS 样酪氨酸激酶 -1 (sFlt-1) 和可溶性内皮糖蛋白。使用两室测定法进行细胞迁移。 LMW 肝素改善了基底滋养层迁移，并诱导生长调节癌基因-α 和 sFlt-1 的有效增加。 ASA不影响基础功能。联合治疗促进迁移，但没有逆转 LMW 肝素诱导的 sFlt-1 效应。抗磷脂抗体增加 IL-8、IL-1β、生长调节癌基因-α、VEGF、PlGF 和可溶内皮糖蛋白的分泌，同时减少细胞迁移以及 IL-6 和 sFlt-1 的分泌。 LMW 肝素可以最好地逆转抗磷脂抗体诱导的细胞因子变化，并部分逆转 IL-8 和 IL-1β 的上调。 LMW 肝素会加剧抗磷脂抗体诱导的血管生成变化，并增加 sFlt-1 的分泌。这些疗法并没有逆转抗磷脂抗体引起的迁移减少。在缺乏抗磷脂抗体的情况下，LMW 肝素会在滋养层中诱导潜在有害的促炎和抗血管生成特征。在存在抗磷脂抗体的情况下，单药 LMW 肝素可能是对抗滋养层炎症的最佳疗法，但也能诱导抗血管生成反应。这些发现可能解释了当前疗法无法持续预防不良后果的原因。
Low molecular weight (LMW) heparin, with or without aspirin (acetylsalicylic acid [ASA]), is used to prevent complications in antiphospholipid syndrome in pregnancy. Our objective was to elucidate the actions of low-dose LMW heparin and ASA on basal and antiphospholipid antibody -induced modulation of trophoblast function. The human first-trimester trophoblast cell line (HTR-8) was treated with or without antiphospholipid antibody in the presence of: 1) no medication, 2) low-dose LMW heparin, 3) low-dose ASA, or 4) combination therapy. Interleukin (IL)-6, IL-8, IL-1β, growth-regulated oncogene-alpha, vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble FMS-like tyrosine kinase-1 (sFlt-1) and soluble endoglin were measured in the supernatant. Cell migration was performed using a two-chamber assay. LMW heparin improved basal trophoblast migration, and induced potent increases in growth-regulated oncogene-alpha and sFlt-1. ASA did not affect basal function. Combined therapy promoted migration, but did not reverse the LMW heparin-induced sFlt-1 effect. Antiphospholipid antibody increased IL-8, IL-1β, growth-regulated oncogene-alpha, VEGF, PlGF, and soluble endoglin secretion, while decreasing cell migration and IL-6 and sFlt-1 secretion. The antiphospholipid antibody-induced cytokine changes were best reversed with LMW heparin, with partial reversal of IL-8 and IL-1β up-regulation. The antiphospholipid antibody-induced angiogenic changes were worsened by LMW heparin, with increased sFlt-1 secretion. The therapies did not reverse antiphospholipid antibody-induced decrease in migration. In the absence of antiphospholipid antibodies, LMW heparin induces potentially detrimental proinflammatory and antiangiogenic profile in the trophoblast. In the presence of antiphospholipid antibodies, single-agent LMW heparin may be the optimal therapy to counter trophoblast inflammation, but also induces an antiangiogenic response. These findings may explain the inability of current therapies to consistently prevent adverse outcomes.