Role of mast cells and their modification by drugs on a disease model for rheumatoid arthritis.

为探讨肥大细胞(MCs)在类风湿关节炎(RA)模型雄性DBA/1J小鼠牛II型胶原(CII)诱导的关节炎(CIA)病理过程中的作用，观察了色甘酸钠2种口服前药的作用。在第一次免疫后第6周出现明显的CIA后，将前药应用于CII免疫的小鼠，持续7或8周。这两种药物都是每天使用一次。未经治疗的免疫小鼠的关节炎症状评分显著升高，而前药治疗可抑制这种升高。放射学评分或指骨破坏也通过前药得到改善。病理组织学观察和血清IgG型抗CII抗体滴度测定也显示前药有改善作用。未经治疗的免疫小鼠血清白介素6水平较高，前药治疗可抑制其升高。免疫未治疗组小鼠关节或相应区域的MCs数量增加，经前药治疗后增加的MCs数量减少。免疫组织化学方法观察前药对CIA小鼠指关节基质金属蛋白酶-2、-3、-9表达的影响。滑膜、软骨和软骨-血管膜交界处的基质金属蛋白酶-2、-3和-9的表达强度和范围均受到显著抑制。综上所述，口服MC稳定剂前药对类风湿关节炎模型有疗效。巨噬细胞数量与关节炎症状以及前药疗效的显著相关性表明，巨噬细胞在关节炎的发病机制中起着重要作用。

To clarify the role of mast cells (MCs) in pathological process of bovine type II collagen (CII)-induced arthritis (CIA) of male DBA/1J mice, which is a model for rheumatoid arthritis, effects of 2 kinds of oral deliverable prodrug of cromolyn sodium were examined. The prodrugs were applied to CII-immunized mice for 7 or 8 weeks, starting after the apparent occurrence of CIA in week 6 after the first immunization. Both drugs were applied once a day. Symptomatic scores of arthritis elevated significantly in non-treated immunized mice, and the elevation of scores was inhibited by prodrugs-treatment. Radiographic scores or phalangeal destruction were also improved by the prodrugs. Pathohistological observation and serum IgG type anti-CII antibody titers measurement also indicated improvement by the prodrugs. Serum interleukin 6 was higher in non-treated immunized mice, and the elevation was inhibited by a prodrug-treatment. MCs number in arthritic or corresponding region was increased in non-treated immunized mice and the increase was reduced by the prodrugs-treatment. Then, the effects of a prodrug on matrix metalloproteinase (MMP)-2, -3 and -9 expression by immunohistochemistry in finger joints of CIA mice were investigated. The extent and intensity of immunostaining of MMP-2, -3 and -9 was dramatically suppressed in synovium, cartilage and cartilage-pannus junction. In conclusion, orally applied prodrugs of a MC stabilizer have an efficacy on rheumatoid arthritis model. Significant correlation of MCs numbers and arthritis symptoms as well as effects of the prodrugs suggests the significant role of MCs in the pathogenesis of arthritis.