缺氧诱导因子-1α和血管内皮细胞生长因子在胶原性关节炎动物模型中的表达与意义

Expression and significance of hypoxia-inducible factor-1a and vascular endothelial growth factor in animal model of collagen induced arthritis

建立Wistar大鼠Ⅱ型胶原诱导性关节炎(CIA)模型,探讨低氧诱导因子-1α(HIF-1α)、血管内皮生长因子(VEGF)在CIA中的表达,为类风湿关节炎的发病机制及治疗前景提供线索。采用50只Wistar大鼠,随机分为对照组与模型组,将牛Ⅱ型胶原与福氏不完全佐剂乳化混匀作为免疫混合物,尾根部皮内注射,建立CIA模型。于造模第21、28、35、42天取踝关节和滑膜组织行HE染色及免疫组化染色,动态观察各项关节炎活动指标和检测HIF-1α和VEGF在CIA关节炎中的表达,并分析两者在CIA中的相关性及HIF-1α与滑膜病理学评分之间的关系。组织形态学和影像学结果显示,CIA大鼠的滑膜组织、关节软骨及骨组织均呈典型的关节炎病变;免疫组化结果显示CIA大鼠关节滑膜层和滑膜下层均表达HIF-1α和VEGF,第21天阳性表达量最高,随病程进展,表达逐渐下降;统计学分析表明HIF-1α和VEGF的表达水平呈正相关(r=0.75,P<0.01),HIF-1α的表达水平与滑膜病理学评分和血管生成评分呈正相关(r_1=0.48,r_2=0.5,P<0.05)。以上结果提示HIF-1α可能通过调控一系列下游靶基因,如VEGF等,促进滑膜增生及血管生成,影响RA的发生与发展。

The expression and significance of hypoxia-inducible factor-1α（HIF-1α） and vascular endothelial growth factor （VEGF） in animal model of collagen-induced arthritis（CIA） were investigated in order to supply clues to the pathogenesis and therapeutic expectations of rheumatoid arthritis（RA）,in which 50 Wistar rats were randomly divided into two groups,one group were immunized with bovine typeⅡcollagen,injected intradermally at the base of rat tail to induce animal model of arthritis, while another group were injected with normal saline served as control.The effects of collagen-induced arthritis were observed by using the arthritis index,histopathology and roentgenography and the expression of HIF-1αand VEGF on synovium was assayed simultaneously at different time point by immunohistochemistry staining.The correlations between of HIF-1αand VEGF,HIF-1αand pathological scores were analyzed respectively.Experimental results of histopathology and roentgenography had shown that there were typical pathological changes in synovium,articular cartilage and bone of CIA rats.The expression of HIF-1αand VEGF on both intimal and subintimal area of synovium were shown,the strongest on the 21st day, and then descent gradually,indicating that the expression of HIF-1αpositively correlated with the expression of VEGF（r= 0.75,P0.01）.The expression of HIF-1αalso positively correlated with the pathological score and angiogenesis score（r_1= 0.48,r_2=0.5,P0.05）.It is concluded that HIF-1αmay affect the pathogenesis of rheumatoid arthritis through synovial hyperplasia and angiogenesis by the induction of the expression of its target genes,such as VEGF gene.