系统性红斑狼疮相关血栓性微血管病血管内皮-间充质细胞转分化的研究

Renal vascular endothelial-mesenchymal transition in systemic lupus erythematosus associated thrombotic microangiopathy

目的:探讨系统性红斑狼疮相关血栓性微血管病(SLE-TMA)肾间质血管内皮细胞表型变化及其与血管病变和间质纤维化之间的关系。方法:30例经肾活检明确诊断的SLE-TMA患者,根据血管组织学改变分为急性TMA和慢性TMA,以正常肾组织血管为对照。内皮细胞CD31、血管内皮钙黏蛋白(VE-cadherin)、α平滑肌肌动蛋白(α-SMA)和转化生长因子β(TGF-β)采用间接免疫荧光双重染色定位,免疫组织化学染色和Image-ProPlus 6.0测量上述分子的表达量,以平均光密度表示其表达强度。Aperio图像分析系统测量肾间质纤维化面积。结果:间接免疫荧光双重染色显示正常血管内膜无α-SMA表达,SLE-TMA血管内皮细胞表达α-SMA。与正常对照组相比,急性TMA组血管内皮CD31和VE-cadherin表达降低(P<0.05),α-SMA表达则显著增高(P<0.01);慢性TMA组内皮细胞CD31、VE-cadherin和TGF-β表达强度均显著低于急性TMA组和正常血管组(P<0.01),α-SMA表达更高(P<0.01)。肾间质血管α-SMA平均光密度与肾间质纤维化面积呈显著正相关(r=0.439,P=0.015),而CD31平均光密度与肾间质纤维化呈显著负相关(r=-0.458,P=0.011)。结论:SLE-TMA血管内皮细胞正常标记物表达减少而α-SMA表达增加,表明内皮细胞向成纤维细胞表型转变,且表达量的变化与血管病变进展相关;肾血管内皮细胞CD31表达减少和α-SMA增加与肾间质纤维化相关。

Objective： To investigate the phenotypic changes of renal vascular endothelial cells and its relationship with the vascular injury and renal interstitial fibrosis in patients with systemic lupus erythematosus associated thrombotic microangiopathy（ SLE-TMA）. Methodology： Biopsies from thirty SLE patients with lupus nephritis and renal vascular TMA were included in this study. Renal vascular TMA lesions were divided into acute and chronic TMA according to histology by light microscopy. Normal renal tissue from nephrectomized kidney of renal cancer was used as normal control.The expression of renal vascular endothelial CD31,vascular endothelial cadherin（ VE-cadherin）,α-smooth muscle actin（ α-SMA） and transforming growth factor-β（ TGF-β） were stained with immunofluorescence and immunohistochemical assays,and computer-assisted image analysis Image-Pro-Plus 6. 0 and ImageS cope（ Aperio） were used to quantitatively analyze the intensity of endothelial marker expression recorded as the mean density（ integral optical density / area of vascular endothelial layer） and the extent of renal interstitial fibrosis respectively. Results： Confocal immunofluorescence microscopy showed increased expression of α-SMA in the vascular endothelial cells in SLE-TMA,while negative endothelialα-SMA expression in normal control. Compared with the normal group,the endothelial expressions of CD31 and VE-cadherin were both significantly reduced in acute TMA group（ P〈0. 05）,whereas the expression of α-SMA increased significantly（ P〈0. 01）. The endothelial CD31,VE-cadherin and TGF-β expressions were significantly lower,while α-SMA expression was significantly higher in chronic TMA group than that in other two groups（ P〈0. 01）. The mean density of endothelial α-SMA expression was positively correlated with（ r = 0. 439,P = 0. 015）,while the expression of endothelial CD31 was negatively correlated with the extent of renal interstitial fibrosis significantly（ r =- 0. 458,P = 0. 011）. Conclusion： Renal vascular endothelial to mesenchymal transition was found in SLE-TMA,which was associated with the renal interstitial fibrosis.