関節リウマチのサイトカインおよび血管増殖因子抑制効果に関する基礎的研究-サイトカインおよびVEGFアンチセンス療法による新しい治療戦略-

血管生成和滑膜细胞病变被认为是慢性和发育性关节炎以及类风湿性关节炎(RA)的基本过程。类固醇类药物和抗风湿药物是目前应用最广泛的类风湿类药物，用于改善类风湿关节炎的临床病程。特别是，我们检测了布比拉明(BUC)、硫代马酸金钠(GST)、甲氨蝶呤(MTX)、柳氮磺吡啶(SASP)和地塞米松(DEX)是否抑制血管内皮生长因子(VEGF)和碱性成纤维细胞生长因子(b-FGF)的产生。结果表明，BUC和DEX单独作用后可分别抑制血管内皮生长因子和mRNA的产生。接下来，我们研究了包括BUC、GST、MTX、SASP和DEX在内的这些DMARD的组合对b-FGF和VEGF产生的影响。单独给予DMARDS或DEX均不能抑制b-FGFs的产生，但SASP和GST联合应用可抑制滑膜细胞b-FGFs的表达。另一方面，所有这些组合都可以…除MTX和SASP联用外，其余LD均可抑制血管内皮细胞生长因子的产生。129例RA患者外周血中，血清血管内皮生长因子水平与C反应蛋白水平呈正相关，服药6个月后较服药前显著降低。通过对RA患者外周血中血管内皮生长因子、b-成纤维细胞生长因子和内皮抑素的检测，用双抗体夹心酶联免疫吸附试验检测了RA患者和非RA患者外周血和关节液中的血管内皮生长因子和血管内皮生长因子。类风湿关节炎患者外周血和关节液中b-FGF和VEGF水平显著高于非类风湿关节炎患者，而内皮抑素水平在类风湿关节炎患者和非类风湿关节炎患者之间无显著差异。这些结果提示，RA的血管生成是血管生成生长因子和血管生成抑制因子之间产生不平衡的结果。我们将研究血管生成或血管生成抑制因子反义寡核苷酸或其他血管生成抑制剂，如TNP 470对SCID小鼠移植的滑膜细胞增殖的抑制作用。较少

Angiogenesis and synovial cell poliferation are thought to be essential processes in chronic and developmental arthritis, as well as rheumatoid arthritis (RA). Steroids and disease modifying antirheumatic drugs are most widely used as modifying the clinical course of RA. In particular, We examined whether bucillamine (BUC), gold sodium thiomalate (GST), methotrexate (MTX), salazosulfapyridine (SASP) an dexamethazone (DEX) inhibit the production of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF). Our results indicated that BUC and DEX could alone inhibit the production of VEGF and mRNA, respectively. Next, we investigated the effect of combinations of these DMARDs including BUC, GST, MTX, SASP and DEX on the production of b-FGF and VEGF. None of the DMARDs or DEX could inhibit b-FGF production when give alone, but a combination of SASP and GST inhibited the prodiction of b-FGF in cultured synoviocytes. On the other hand, all of these combinations cou … More ld inhibit VEGF production except the combinationof MTX and SASP. In the peripheral bloos from obtained 129 RA patients, the serum VEGF levels were correlated with CRP (C-reactive protein) and were found to be significantly decreased 6 months after the commencement of medication compared to their levels before. These results in vitro were supported by the observations in the peripheral blood of patients with RA, that is, in vivo.We mesured the VEGF and b-FGF, and endostatin in peripheral blood and joint fluid obtained from patients with RA and non RA patients using ELISA. The b-FGF and VEGF levels in the peripheral blood and joint fluid of patients with RA were significantly higher than those in the samples from patients without RA, but the endostatin levels were similar and not significantly different between patients with RA and without RA. These results suggested angiogenesis in RA occurs as a result of an imbalance in production between angiogenic growth factors and angiogenesis inhibitors. We will investigate angiogenesis or the inhibitory effects the synovial cell proliferation transplanted in SCID mouse by VEGF antisense or the other angiogenesis inhibitors, like TNP 470. Less