Recurring episodes of acute pain, also referred to as vaso-occlusive crises (VOC), are characteristic of sickle cell disease (SCD), during which pro-inflammatory cytokines, chemokines, adhesion markers and white cell count, some already elevated at steady state, increase further. Hydroxyurea (HU) is licensed by the FDA for reducing frequency of VOCs in SCD; increased fetal hemoglobin (HbF) together with reduction of the neutrophil count and circulating inflammatory markers, contribute to its clinical efficacy. Here, using paired plasma samples from HbSS patients (in steady-state and VOC) we determined that despite HU treatment, the SCD environment remained highly inflammatory and particularly at VOC, triggered neutrophil activity. While neutrophil extracellular traps (NETs) induction by the steady state plasmas were comparable to that of plasma from healthy donors, the NETs response triggered by crisis plasmas was significantly increased over that of the steady state (P = 0.0124*). Levels of IL-6 and IL-1α, IL-1ra/IL1F3 and adhesion molecule P-selectin were significantly increased in the VOC plasma when compared with steady state plasma. Higher levels of IL-6 and IL-1ra were also found in the crises samples that yielded an increased NETs response suggesting that increased NETs production associated with increased levels of the inflammatory products of the IL-6 family and regulators of IL-1 family of cytokines during sickle VOCs.

中文翻译：

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镰状细胞血管闭塞危象期间促炎细胞因子与 NETosis 相关

反复发作的急性疼痛，也称为血管闭塞性危象 (VOC)，是镰状细胞病 (SCD) 的特征，在此期间促炎细胞因子、趋化因子、粘附标志物和白细胞计数，有些在稳态时已经升高，进一步增加。羟基脲 (HU) 获得 FDA 许可，用于降低 SCD 中 VOC 的频率；增加的胎儿血红蛋白 (HbF) 以及中性粒细胞计数和循环炎症标志物的减少，有助于其临床疗效。在这里，使用来自 HbSS 患者（稳态和 VOC）的配对血浆样本，我们确定尽管 HU 治疗，但 SCD 环境仍然具有高度炎症性，尤其是在 VOC 下，会触发中性粒细胞活动。虽然稳态血浆诱导的中性粒细胞胞外陷阱 (NETs) 与来自健康供体的血浆相当，但危机血浆引发的 NETs 反应比稳态显着增加 (P = 0.0124*)。与稳态血浆相比，VOC 血浆中 IL-6 和 IL-1α、IL-1ra/IL1F3 和粘附分子 P-选择素的水平显着增加。在产生 NETs 反应增加的危机样本中也发现了更高水平的 IL-6 和 IL-1ra，这表明 NETs 产量增加与 IL-6 家族炎症产物和 IL-1 家族调节剂水平增加有关。镰状VOCs期间的细胞因子。与稳态血浆相比，VOC 血浆中 IL-6 和 IL-1α、IL-1ra/IL1F3 和粘附分子 P-选择素的水平显着增加。在产生 NETs 反应增加的危机样本中也发现了更高水平的 IL-6 和 IL-1ra，这表明 NETs 产量增加与 IL-6 家族炎症产物和 IL-1 家族调节剂水平增加有关。镰状VOCs期间的细胞因子。与稳态血浆相比，VOC 血浆中 IL-6 和 IL-1α、IL-1ra/IL1F3 和粘附分子 P-选择素的水平显着增加。在产生 NETs 反应增加的危机样本中也发现了更高水平的 IL-6 和 IL-1ra，这表明 NETs 产量增加与 IL-6 家族炎症产物和 IL-1 家族调节剂水平增加有关。镰状VOCs期间的细胞因子。