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塞隆骨治疗类风湿性关节炎分子机理研究
其他题名The experimental study of molecular mechanism about extraction of Myospalax fontanieri bone against rheumatoid arthritis
赵晓辉
学位类型硕士
导师陶燕铎
2007-06-09
学位授予单位中国科学院西北高原生物研究所
学位授予地点西北高原生物研究所
关键词塞隆骨提取物(slg-b) 类风湿性关节炎 胶原诱导的关节炎 分子机理 Rt-pcr 细胞因子 炎症因子
摘要类风湿性关节炎是一种常见的以关节损伤为主的慢性、多发性炎症性疾病,其病变以滑膜组织炎性细胞浸润、滑膜细胞增殖、血管翳形成和软骨及软骨下骨质破坏为主要免疫病理表现,最终导致受累关节发生畸形而出现关节废用、致残。本实验研究塞隆骨提取物(SLG-B)蛋白对二甲苯所致的小鼠急性耳肿胀、蛋清致大鼠足肿胀模型及DNFB(二硝基氟苯)致的迟发型超敏反应(DTH)的治疗作用。应用CFA诱导活化小鼠腹腔巨噬细胞,在细胞水平对SLG-B对腹腔巨噬细胞功能的影响进行研究。利用牛Ⅱ型胶原诱导小鼠关节炎(CIA),从整体、细胞、分子不同水平对SLG-B的作用机理进行研究,以期探讨SLG-B蛋白治疗类风湿性关节炎的分子作用机理,为开发更好的相关药物提供实验依据。结果表明: 1. SLG-B对二甲苯所致的小鼠耳肿胀的影响 实验结果显示:SLG-B对二甲苯所致的急性炎症模型具有明显的抑制作用。 2. SLG-B对蛋清所致的大鼠炎症模型的影响 SLG-B蛋白能够抑制蛋清所致的大鼠脚肿胀度,但作用不明显。 3. SLG-B对T细胞介导的DTH反应的影响 实验结果显示:SLG-B对DTH小鼠耳肿胀具有明显的抑制作用,各剂量均对DNFB所致的小鼠耳肿胀炎症模型有明显的抑制作用。 4. SLG-B对CFA诱导活化的小鼠腹腔巨噬细胞功能的影响 SLG-B体内给药均能够能显著抑制CFA诱导的巨噬细胞向腹腔的浸润,能抑制巨噬细胞在LPS及IFN-γ刺激下生成细胞因子(IL-12p40、IL-1、IL-6 、TNF-α)。这应是其治疗类风湿性关节炎的作用机理之一。 5. SLG-B对牛Ⅱ型胶原诱导的小鼠关节炎的治疗作用及机理研究 本实验研究了SLG蛋白治疗类风湿性关节炎的分子作用机制。结果显示: SLG-B蛋白的0.18g/kg,0.36g/kg两种剂量体内给药均能明显的抑制牛Ⅱ型胶原诱导关节炎的发生,能够显著减轻关节炎的各种症状,达到治疗的目的。组织病理切片发现SLG-B治疗后能够改善骨关节病变,关节软骨及其下的骨小梁与正常组接近,血管翳明显减少,且治疗效果好于阳性对照药MTX(1mg/kg)。在对小鼠脾细胞体外培养增殖实验中发现SLG-B蛋白在加抗原和不加抗原的情况下都能够明显的抑制关节炎小鼠脾细胞的增殖。在对细胞因子的测定中发现SLG-B能够显著抑制IL-2、IFN-γ、L-12 、TNF-ɑ细胞因子的产生。同时通过RT-PCR发现只有SLG-B能够抑制小鼠腹腔巨噬细胞IL-1、IL-6及iNOS mRNA的表达。这应是SLG-B在小鼠关节炎中表现治疗效果的分子基础。 以上结果表明:SLG-B蛋白具有抗炎、免疫抑制作用,能够防治类风湿性关节炎,其分子作用基础主要与抑制巨噬细胞向炎性部位迁移及抑制抗原递呈,抑制巨噬细胞产生炎性细胞因子。同时与抑制T淋巴细胞增值,减少T细胞和巨噬细胞分泌炎性因子的作用有关。
其他摘要In this paper applied the DNFB-induced ear swelling of mice, feet swell by egg white induced and we also observed its effect on T cell-mediated DNFB-induced delayed type hypersensitivity reaction (DTH ) reaction. On the gross, cellular and molecular levels, we applied CFA induced mice celiac macrophages and established the collagen-induced athritis ( CIA) to research the effects of prevent and cure RA for SLG-B protein, we also use the cell culture technology to study the influence of effects of cycotoxicity and influences of T and MΦ cell proliferation and the concentrations of IL-1、IL-6、IL-12p40、IFN-γ and TNF-αwere deceted by ELISA .In a word, we aim to discuss the mechanism of extraction of Myospalax fontanieri bone (SLG-B)against RA from the gross, cellular and molecular levels. With the completion of this research, it makes possible to develop novel interrelated drug against RA. The results were showed as follows: 1. Effects of SLG-B on induced mice ear swell SLG-B significantly inhibited DNFB-induced ear swell of mice vs model (p<0.05,p<0.01),showed significantly anti-inflammatory effect. 2. SLG-B inhibited feet swell by egg white induced rats The result showed that SLG protein had the well effect of prevention and cure on AA. SLG-B protein could inhibit joints of the forepart primary and secondary affect swell. 3. SLG-B effect on T cell-mediated DNFB-induced DTH reaction SLG-B in a dose-dependent manner significantly inhibited DNFB-induced ear swell of mice vs model (p<0.05,p<0.01) 4. SLG-B suppressed Complete Freund’s adjuvant (CFA) induced antigen-specific immune responses in mice. Based on the previous experiment we investigated the molecular mechanism of SLG against RA. SLG-B have immunosuppressive on mice celiac macrophages, and markedly decrease production of inflammatory Cytokine, IL-1、IL-6、IL-12p40,and TNF-α.this may be one of therapy mechanism on rheumatoid arthritis. 5. Efects of SLG-B on CⅡ-induced rheumatoid arthritis in mice and the mechanism was investigated. In vivo treatment with SLG-B dose-dependently suppressed CIA mice arthritis index in vitro. We have succesefully establisted the mice model of CIA to research effects of prevention and cure of SLG-B. The results showed that SLG-B had the well effect of prevention and cure on CIA and could inhibit joints of the forepart affect swell. At the same time SLG-B could inhibit hyperplasia of thesynovial lining cells, an inflammatory cell infiltrate and destructive changes of connective tissue and cartilage of joints of the affect pathology.On the basis of above, we have investigated the molecular immunological mechanism about SLG-B against CIA. The experimental results showed that SLG-B could suppress the proliferation of T lymphocytes stimulated with ConA. They all had the inhibitory effect on IL-2、IFN-γ、IL-12 and TNF-ɑ produced in cultured T cell and peritoneal macrophages in CIA mice. It had the inhibitory effect on IL-1β、IL-6 and iNOSmRNA gene expression in peritoneal macrophages of CIA mice in vivo. Our result showed SLG-B protein have anti-inflammatory ease pain and immunosuppressive effects and against RA. It is the main molecular mechanism of against RA that suppressed soakage of macrophage to inflammatory tissue and inhibited the APC function and the expression of inflammatory cytokines.
页数57
语种中文
文献类型学位论文
条目标识符http://210.75.249.4/handle/363003/3110
专题中国科学院西北高原生物研究所
推荐引用方式
GB/T 7714
赵晓辉. 塞隆骨治疗类风湿性关节炎分子机理研究[D]. 西北高原生物研究所. 中国科学院西北高原生物研究所,2007.
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