Hounkpe Bidossessi Wilfried, Chenou Francine, Domingos Igor de Farias, Cardoso Evilazio Cunha, Costa Sobreira Marcondes José de Vasconcelos, Araujo Aderson S, Lucena-Araújo Antonio Roberto, da Silva Neto Pedro Vieira, Malheiro Adriana, Fraiji Nelson Abrahim, Costa Fernando Ferreira, Bezerra Marcos André C, Santos Magnun Nueldo Nunes, De Paula Erich Vinicius
School of Medical Sciences University of Campinas Campinas Brazil.
Federal University of Rio Grande do Norte (UFRN) Recife Brazil.
Res Pract Thromb Haemost. 2020 Dec 16;5(1):204-210. doi: 10.1002/rth2.12463. eCollection 2021 Jan.
Recent evidence suggests that generation of neutrophil extracellular traps (NETosis), one of the components of immunothrombosis, is associated with the pathogenesis of both venous thromboembolism and sickle cell disease (SCD). NETosis is a complex process regulated by several proteins such as peptidyl arginine deaminase 4 (PADI4), neutrophil elastase (ELANE), and myeloperoxidase (MPO). Among these regulators, PADI4 is responsible of histone citrullination, an essential step for NETosis. Accordingly, its inhibition has been recently cited as a promising therapeutic strategy for diseases such as SCD. Although attractive, this strategy requires supportive evidence of its role in the pathogenesis of SCD.
Patients from two independent cohorts were enrolled in this study. Samples were obtained at steady state (53 patients) or during acute episodes of vaso-occlusive crisis (VOC; 28 patients) in patients from cohort 1. mRNA was extracted from granulocytes to analyze , , and expression by qPCR. Furthermore, plasma activity of PADI4 was assessed from an independent cohort in 15 patients, within 24 hours from admission for VOC. Race-matched healthy individuals from the same geographic regions were used as controls for each cohort.
Higher levels of gene expression of and were observed during VOC. Furthermore, plasma activity of PADI4 was higher in acute VOC when compared to healthy individuals. These results demonstrate that NETosis regulators are modulated during acute VOC, and pave the way for studies of inhibition as a therapeutic strategy for acute VOC in SCD.
最近的证据表明，免疫血栓形成的组成部分之一中性粒细胞胞外诱捕网（NETosis）的产生与静脉血栓栓塞和镰状细胞病（SCD）的发病机制相关。NETosis是一个由几种蛋白质调节的复杂过程，如肽基精氨酸脱氨酶4（PADI4）、中性粒细胞弹性蛋白酶（ELANE）和髓过氧化物酶（MPO）。在这些调节因子中，PADI4负责组蛋白瓜氨酸化，这是NETosis的一个关键步骤。因此，其抑制作用最近被认为是治疗SCD等疾病的一种有前景的治疗策略。尽管很有吸引力，但该策略需要其在SCD发病机制中的作用的支持性证据。
本研究纳入了来自两个独立队列的患者。在队列1的患者处于稳定状态时（53例患者）或血管闭塞性危机（VOC）急性发作期间（28例患者）采集样本。从粒细胞中提取mRNA，通过qPCR分析PADI4、ELANE和MPO的表达。此外，在VOC入院后24小时内，从一个独立队列的15例患者中评估PADI4的血浆活性。来自相同地理区域的种族匹配的健康个体用作每个队列的对照。
在VOC期间观察到PADI4和ELANE的基因表达水平较高。此外，与健康个体相比，急性VOC时PADI4的血浆活性更高。这些结果表明，在急性VOC期间，NETosis调节因子受到调节，并为研究抑制PADI4作为SCD急性VOC的治疗策略铺平了道路。
