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

肥大细胞的作用及其药物修饰在类风湿性关节炎疾病模型中的作用。

• 批准号: 11670088
• 负责人: KOBAYASHI Yuta
• 金额: $ 2.3万
• 依托单位: Shimane Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670088/
• 关键词: rheum atoid arthritis; mast cells; collagen-induced arthritis mice; cromolyn sodium; synovium; Matrix Metalloproteinase; Cytokines; コラーゲン誘発関節炎; マウス; 中医薬; Matriix Metalloproteinase; インターロイキン6

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.

为了阐明肥大细胞（MC）在雄性 DBA/1J 小鼠（类风湿性关节炎模型）牛 II 型胶原（CII）诱导的关节炎（CIA）病理过程中的作用，检测了 2 种口服可递送的色甘酸钠前药的作用。从第一次免疫后第 6 周明显出现 CIA 后开始，将前药应用于 CII 免疫小鼠 7 或 8 周。两种药物每天使用一次。在未经治疗的免疫小鼠中，关节炎症状评分显着升高，并且前药治疗抑制了评分的升高。前药也改善了放射照相评分或指骨破坏。病理组织学观察和血清IgG型抗CII抗体滴度测量也表明前药的改善。未经治疗的免疫小鼠血清白细胞介素 6 较高，并且前体药物治疗可抑制该升高。在未治疗的免疫小鼠中，关节炎或相应区域的 MC 数量增加，并且通过前药治疗减少了增加。然后，通过免疫组织化学研究前药对 CIA 小鼠手指关节中基质金属蛋白酶 (MMP)-2、-3 和 -9 表达的影响。 MMP-2、-3和-9免疫染色的范围和强度在滑膜、软骨和软骨-血管翳连接处显着受到抑制。总之，口服MC稳定剂的前药对类风湿性关节炎模型具有疗效。 MC 数量与关节炎症状以及前药作用的显着相关性表明 MC 在关节炎发病机制中发挥着重要作用。

项目成果

Kobayashi, Y.: "Effects of orally available prodrug of cromoglycic acid on collagen-induced arthritis mice. (in Japanese)"Folia Pharmacology Japan. 114(S1). 154-158 (1999)

Kobayashi, Y.：“口服色甘酸前药对胶原诱导的关节炎小鼠的影响。（日语）”Folia Pharmacology Japan。

Kobayashi, Y.: "Aging of endocrine system. (in Japanese)"Gerontology ; overview and perspective University of Tokyo press. 145-158 (1999)

Kobayashi, Y.：“内分泌系统的老化。（日语）”老年学；

Wong,D-Q: "Effective inhibition of tissue angiotensin-converting enzyme attenuates pressure-overload aortic hypertrophy in early stage in rats."Shimane Journal of Medical Science. 17(2). 51-59 (1999)

Wong，D-Q：“有效抑制组织血管紧张素转换酶可减轻大鼠早期压力超负荷的主动脉肥大。”岛根医学科学杂志。

Kakizoe, E.: "Increases of mast cells and chymase in fibroproliferative paws of collagen-induced arthritic mice."Inflammation Research. 48(6). 318-324 (1999)

Kakizoe, E.：“胶原诱导的关节炎小鼠的纤维增殖性爪子中肥大细胞和食糜酶增加。”炎症研究。

Wang, D-Q.: "Differential suppression of pressure-overload cardiac and aortic hypertrophy in rats by angiotensin-converting enzyme inhibitors."Japanese Journal od Pharmacology. 80(4). 333-342 (1999)

Wang, D-Q.：“血管紧张素转换酶抑制剂对大鼠压力超负荷心脏和主动脉肥大的差异抑制。”日本药理学杂志。