Thalidomide Effects in Patients with Hereditary Hemorrhagic Telangiectasia During Therapeutic Treatment and in Fli-EGFP Transgenic Zebrafish Model.
Thalidomide Effects in Patients with Hereditary Hemorrhagic Telangiectasia During Therapeutic Treatment and in Fli-EGFP Transgenic Zebrafish Model.
复制标题
DOI：
10.4103/0366-6999.169068
复制
发表时间：
2015-11-20
影响因子：
6.1
通讯作者：
Zhang GS
中科院分区：
文献类型：
--
作者：
Peng HL;Yi YF;Zhou SK;Xie SS;Zhang GS
遗传性出血性毛细血管扩张症（HHT）是一种常染色体显性遗传疾病，其特征是反复鼻出血、粘膜皮肤毛细血管扩张和动静脉畸形。传统治疗HHT的疗效非常有限。本研究旨在探讨沙利度胺对HHT患者的治疗作用以及对FLI-EGFP转基因斑马鱼模型的影响。根据Shovlin标准诊断HHT。5例HHT患者接受沙利度胺（100 mg/d）治疗。采用鼻出血严重程度评分（ESS）、毛细血管扩张点、肝脏CT血管造影（CTA）评价沙利度胺的临床疗效。研究了Fli-EGFP斑马鱼模型对沙利度胺对血管生成的影响。采用实时荧光定量聚合酶链反应（PCR）、酶联免疫吸附试验（ELISA）和免疫印迹法（Western blotting）检测患者治疗前、治疗6个月后外周血单个核细胞和血浆中转化生长因子β 3（TGF-β3）mRNA和血管内皮生长因子（VEGF）蛋白的表达。反应停治疗前后ESS评分分别为6.966 ± 3.093和1.799 ± 0.627（P = 0.009）。病例2的CTA检查显示肝动脉近端变小，肝动脉侧支循环减少或停止。Fli-EGFP斑马鱼模型表现为血管发育不连续和血管闭塞（7/10），5例患者的TGF-β3 mRNA表达在沙利度胺治疗后降低。HHT患者血浆VEGF蛋白表达下调。沙利度胺通过下调HHT患者TGF-β3和VEGF的表达逆转毛细血管扩张并控制鼻出血。它还导致斑马鱼模型中的血管重塑。
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by recurrent epistaxis, mucocutaneous telangiectasia, and arteriovenous malformations. The efficacy of traditional treatments for HHT is very limited. The aim of this study was to investigate the therapeutic role of thalidomide in HHT patients and the effect in FLI-EGFP transgenic zebrafish model. HHT was diagnosed according to Shovlin criteria. Five HHT patients were treated with thalidomide (100 mg/d). The Epistaxis Severity Score (ESS), telangiectasia spots, and hepatic computed tomography angiography (CTA) were used to assess the clinical efficacy of thalidomide. The Fli-EGFP zebrafish model was investigated for the effect of thalidomide on angiogenesis. Dynamic real-time polymerase chain reaction assay, ELISA and Western blotting from patient's peripheral blood mononuclear cells and plasma were used to detect the expression of transforming growth factor beta 3 (TGF-β3) messenger RNA (mRNA) and vascular endothelial growth factor (VEGF) protein before and after 6 months of thalidomide treatment. The average ESS before and after thalidomide were 6.966 ± 3.093 and 1.799 ± 0.627, respectively (P = 0.009). The “telangiectatic spot” on the tongue almost vanished; CTA examination of case 2 indicated a smaller proximal hepatic artery and decreased or ceased hepatic artery collateral circulation. The Fli-EGFP zebrafish model manifested discontinuous vessel development and vascular occlusion (7 of 10 fishes), and the TGF-β3 mRNA expression of five patients was lower after thalidomide therapy. The plasma VEGF protein expression was down-regulated in HHT patients. Thalidomide reverses telangiectasia and controls nosebleeds by down-regulating the expression of TGF-β3 and VEGF in HHT patients. It also leads to vascular remodeling in the zebrafish model.