沙利度胺治疗胃肠道血管畸形所致消化道出血的机制研究

Study on the Mechanism of Thalidomide for the Treatment of Gastrointestinal Bleeding Caused by Gastrointestinal Vascular Malformation

【目的】探讨沙利度胺治疗胃肠道血管畸形所致消化道出血的作用机制。【方法】采用免疫组化法检测90例GIVM 所致消化道出血患者，及30例健康人肠黏膜中促血管生成素‐2（Ang‐2）、Notch‐1、DLL4的表达；采用RT‐PCR及Western blot检测50 mg／L、100 mg／L、200 mg／L沙利度胺对HUVEC细胞Ang‐2、Notch‐1、DLL4基因mRNA及蛋白表达的影响。【结果】与溶剂对照组比较，50 mg／L沙利度胺组中Notch‐1的mRNA表达量减少，100 mg／L沙利度胺组中Ang‐2，Notch‐1的mRNA表达量减少，差异具有统计学意义（ P ＜0．05），200 mg／L沙利度胺组中Ang‐2，Notch‐1，DII4的mRNA表达量减少，差异均有统计学意义（ P ＜0．05）。与溶剂对照组比较，50 mg／L沙利度胺组中 Ang‐2、Notch‐1的蛋白表达量下降，100 mg／L ，200 mg／L沙利度胺组中的 Ang‐2， Notch‐1，DLL4的蛋白表达量均下降，差异都具有统计学意义（ P ＜0．05）。GIVM组织中血管扩张扭曲。Ang‐2的表达明显增高。DLL4和Notch‐1的表达在病变组织中亦明显增高。而胃肠道血管畸形（GIVM ）患者非病变组织及健康体检者正常肠黏膜组织中Ang‐2、Notch‐1、DLL4均呈弱阳性（＋）或阴性表达。【结果】GIVM 与Ang‐2、DLL4和Notch‐1的表达密切相关，且沙利度胺可抑制Ang‐2、DLL4和Notch‐1的mRNA及蛋白的表达。

[Objective]To explore the action mechanism of thalidomide for the treatment of gastrointestinal bleeding caused by gastrointestinal vascular malformation （GIVM ） .[Methods]The expression of Ang‐2 ,Notchl and DLL4 in intestinal mucosa of 90 patients with gastrointestinal bleeding caused by GIVM and 30 healthy per‐sons were detected by using immunohistochemical method .RT‐PCR and Western blot were used to detect the im‐pact of 50mg/L ,100mg/L and 200mg/L thalidomide on the mRNA and protein expression of Ang‐2 ,Notchl and DLL4 gene in HUVEC cells .[Results]Compared with solvent control group ,the mRNA expression of Notch1 in 50mg/L thalidomide group was reduced ,and the mRNA expression of Ang‐2 and Notch1 in 100mg/L thalidomide group were reduced ,and there was significant difference（ P 〈0 .05） .The mRNA expression of Ang‐2 ,Notch1 and DLL4 in 200mg/L thalidomide group were reduced ,and there was significant difference（ P 〈0 .05） .Com‐pared with solvent control group ,the protein expression of Ang‐2 and Notch1 in 50mg/L thalidomide group were reduced ,and the protein expression of Ang‐2 ,Notch1 and DLL4 in 100mg/L and 200mg/L thalidomide group were reduced ,and there was significant difference（ P 〈0 .05） .The expression of Ang‐2 in vasodilation distortion tissues of GIVM was increased obviously ,and the expression of DLL4 and Notchl in the diseased tissues was also increased obviously .The expression of Ang‐2 ,Notchl and DLL4 in non‐diseased tissues of GIVM patients and normal intestinal mucosa tissues of healthy persons were weakly positive （＋ ） or negative .[Conclusion]GIVM is closely associated with the expression of Ang‐2 ,DLL4 and Notchl .Thalidomide can inhibit the mRNA and protein expression of Ang‐2 ,DLL4 and Notchl .