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增殖被认为是慢性和发育性关节炎以及类风湿关节炎（RA）的必要过程。类固醇和疾病改善抗风湿药物被广泛用于改善RA的临床病程。我们特别研究了buillamine （BUC）、gold sodium thimalate （GST）、甲氨蝶呤（MTX）、salazosulfapyridine （SASP）和dexamethazone （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。我们的研究结果表明，BUC和DEX分别可以抑制VEGF和mRNA的产生。接下来，我们研究了BUC、GST、MTX、SASP和DEX等DMARDs联合使用对b-FGF和VEGF生成的影响。单独给药时，DMARDs和DEX均不能抑制b-FGF的产生，但SASP和GST联合给药可抑制培养滑膜细胞b-FGF的产生。另一方面，除MTX和SASP联合外，所有这些联合都能更有效地抑制VEGF的产生。在获得的129例RA患者的外周血中，血清VEGF水平与CRP （c -反应蛋白）相关，并且在开始用药6个月后与用药前相比显著降低。这些体外结果得到了RA患者外周血（即体内）观察结果的支持。我们用ELISA法测定了RA患者和非RA患者外周血和关节液中的VEGF、b-FGF和内皮抑素。RA患者外周血和关节液中b-FGF和VEGF水平明显高于非RA患者样本，但内皮抑素水平相似，RA患者和非RA患者之间无显著差异。这些结果表明，RA中的血管生成是由于血管生成生长因子和血管生成抑制剂之间的不平衡而发生的。我们将研究VEGF反义或其他血管生成抑制剂（如TNP 470）对SCID小鼠移植滑膜细胞增殖的血管生成或抑制作用。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