Department of Pediatrics, Stony Brook University School of Medicine, 100 Nicolls Road, Stony Brook, NY 11794, USA.
Department of Pediatrics, Division of Neonatology, NYU-Winthrop Hospital, 259 First Street, Mineola, NY 11501, USA.
Placenta. 2017 Oct;58:60-66. doi: 10.1016/j.placenta.2017.08.006. Epub 2017 Aug 12.
Intrauterine infection and inflammation during pregnancy, which leads to up-regulation of inflammatory cytokines and prostaglandin synthesis, has been implicated in the pathogenesis of preterm delivery and other pregnancy complications. Effective preventive and therapeutic strategies to reduce these outcomes are lacking to date. Pentoxifylline (PTX) is a non-specific phosphodiesterase inhibitor which raises intracellular cyclic adenosine monophosphate and decreases production of pro-inflammatory mediators while enhancing anti-inflammatory cytokines. We hypothesized that pentoxifylline will decrease lipopolysaccharide (LPS)-induced pro-inflammatory cytokines production in human placental explants.
Placental explants derived from normal second trimester human placentas were treated with PTX, stimulated with LPS and cultured at 37 °C in 5% CO. Conditioned media were assayed for pro- and anti-inflammatory mediators with multiplex immunoassays or ELISA, and explant tissues for mRNA with real time PCR. Means of PTX-treated and untreated samples were compared using paired t tests and Wilcoxon-signed rank tests.
PTX preferentially inhibited placental expression and production of LPS-induced pro-inflammatory cytokines including TNF-α (25461 vs. 1908 pg/ml, p < 0.001), IL-1β (2921 vs. 1067 pg/ml, p < 0.001) and IFN-γ (2190 vs 427 pg/ml, p < 0.001) with relative preservation of anti-inflammatory mediators. The suppressive effects on LPS-induced placental inflammation were independent of the timing of PTX administration in relation to LPS-induced stimulation.
Our study suggests that PTX attenuates the LPS-induced pro-inflammatory milieu in human placental explants. We speculate that PTX may have utility as a candidate anti-inflammatory agent for prophylaxis and/or treatment of human placental inflammation.
妊娠期间的宫内感染和炎症会导致炎症细胞因子和前列腺素合成的上调，这与早产和其他妊娠并发症的发病机制有关。迄今为止，还缺乏有效的预防和治疗策略来减少这些后果。己酮可可碱（PTX）是一种非特异性磷酸二酯酶抑制剂，可提高细胞内环腺苷酸单磷酸水平，减少促炎介质的产生，同时增强抗炎细胞因子。我们假设己酮可可碱将降低脂多糖（LPS）诱导的人胎盘组织中促炎细胞因子的产生。
从正常妊娠中期的人胎盘获得胎盘组织，并使用 PTX 处理，用 LPS 刺激，并在 37°C 和 5%CO 下培养。用多重免疫测定法或 ELISA 检测条件培养基中的促炎和抗炎介质，并用实时 PCR 检测组织中的 mRNA。使用配对 t 检验和 Wilcoxon 符号秩检验比较 PTX 处理和未处理样品的平均值。
PTX 优先抑制 LPS 诱导的促炎细胞因子的胎盘表达和产生，包括 TNF-α（25461 与 1908 pg/ml，p < 0.001）、IL-1β（2921 与 1067 pg/ml，p < 0.001）和 IFN-γ（2190 与 427 pg/ml，p < 0.001），同时相对保留抗炎介质。PTX 对 LPS 诱导的胎盘炎症的抑制作用与 LPS 诱导刺激时 PTX 给药的时间无关。
我们的研究表明，PTX 可减轻人胎盘组织中 LPS 诱导的促炎环境。我们推测，PTX 可能作为预防和/或治疗人类胎盘炎症的候选抗炎剂具有一定的应用价值。
