Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
Thromb Haemost. 2018 Jan;118(1):161-173. doi: 10.1160/TH17-04-0275. Epub 2018 Jan 5.
Sinusoidal obstruction syndrome is a life-threatening complication that can occur after haematopoietic stem cell transplantation. Defibrotide (DF) has been approved for the treatment of individuals with severe sinusoidal obstruction syndrome following haematopoietic stem cell transplantation in the European Union and the United States. However, the precise mechanisms by which DF protects endothelial cells remain to be elucidated. In this study, we found that DF stimulated angiogenesis in vitro and in vivo as assessed by vascular tube formation, scratch-wound repair and Matrigel plug assays. These effects were associated with an activation of pro-survival signalling pathways, including AKT (protein kinase B), ERK (extracellular signal-regulated kinases) and p38. More importantly, DF alleviated calcineurin inhibitor-induced growth inhibition and apoptosis of human umbilical vein endothelial cells and human hepatic sinusoidal endothelial cells in parallel with upregulation of anti-apoptotic protein B-cell lymphoma-extra-large (Bcl-xL), which was mediated by AKT (protein kinase B). Notably, these effects were abrogated when Bcl-xL was depleted by small interfering RNA (ribonucleic acid). In addition, DF counteracted calcineurin inhibitor-induced activation of nuclear factor-κB and Janus kinase 2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) signalling and production of cytokines in vascular endothelial cell-derived EA.hy926 cells. Taken together, DF has pro-angiogenic, anti-apoptotic and anti-inflammatory effects on endothelial cells. DF is a potentially useful agent to prevent the development of, and treat individuals with, endothelial cell injury-related complications after haematopoietic stem cell transplantation.
窦状隙阻塞综合征是造血干细胞移植后发生的一种危及生命的并发症。在欧盟和美国，已批准使用去纤维肽（defibrotide，DF）治疗造血干细胞移植后发生严重窦状隙阻塞综合征的患者。然而，DF 保护内皮细胞的确切机制仍有待阐明。在这项研究中，我们发现 DF 通过血管管腔形成、划痕修复和 Matrigel plugs 测定，在体外和体内均能刺激血管生成。这些作用与 AKT（蛋白激酶 B）、ERK（细胞外信号调节激酶）和 p38 等促生存信号通路的激活有关。更重要的是，DF 减轻了钙调神经磷酸酶抑制剂诱导的人脐静脉内皮细胞和人肝窦内皮细胞的生长抑制和凋亡，同时上调了抗凋亡蛋白 B 细胞淋巴瘤-extra-large（Bcl-xL），这是由 AKT（蛋白激酶 B）介导的。值得注意的是，当通过小干扰 RNA（ribonucleic acid，siRNA）耗尽 Bcl-xL 时，这些作用被消除。此外，DF 对抗钙调神经磷酸酶抑制剂诱导的核因子-κB 和 Janus 激酶 2（JAK2）/信号转导和转录激活因子 3（STAT3）信号的激活和血管内皮细胞衍生的 EA.hy926 细胞中细胞因子的产生。总之，DF 对内皮细胞具有促血管生成、抗凋亡和抗炎作用。DF 是一种潜在有用的药物，可预防造血干细胞移植后内皮细胞损伤相关并发症的发生，并用于治疗此类并发症。
