| Rheumatoid arthritis (RA) is a symmetry around a number of chronic inflammatory disease of the joints as the major systemic manifestations of connective tissue disease, is also a common genital refractory non-specific autoimmune diseases. The main pathological changes of chronic synovial inflammation, inflammatory cells infiltration, excessive proliferation of synovial cells and capillary endothelial cells constitute a characteristic pannus, erosion around the tendons, ligaments, cartilage and bone, leading to progressive joint damage , deformity and loss of function, the body other systems are also affected to varying degrees, on human health and pose a serious threat to the quality of life.Because the disease had chronic progressive erosion features,2 years in the onset, if not treated can occur irrevocable destruction of bone joints, eventually leading to ankylosis deformities, high disability ratio to patients with long-term physical and mental suffering. However, because the cause is not clear, the pathogenic mechanism unclear, although there are a variety of therapeutic drugs and means, but can not cure or effective prevention, and clinical practice are used to treat rheumatoid arthritis with different types of drug release degree of toxicity, side effects, or expensive, not suitable for patients with long-term treatment. Therefore, if selected on the fibroblast-like synoviocytes and inhibit efficient, low toxicity of natural medicines on the treatment of rheumatoid arthritis will play a tremendous role in promoting.In this day and age, tumor targeted therapy more and more developed, such as the use of such theories can be used in the treatment of rheumatoid arthritis, that is, in intracellular signal transduction at blocking the excessive proliferation of synovial cells, so as to achieve a fundamental control the disease, the elimination of joint deformity and disability purposes.Future research and development of such drugs will be the trend of the times.Resveratrol belongs to non-flavonoid polyphenol compounds, mainly in grape skin and grape seeds with a variety of beneficial biological activity of human health, such as anti-inflammatory anti-bacterial, anti-oxidation, induced cell cycle arrest, induction of cell wither perish, inhibiting angiogenesis, immune regulation and anti-tumor and so on, and drug side effects, the distribution of a wide range of mature extraction process, with high medicinal value and market prospects.Research has shown that resveratrol in a variety of cell has a strong anti-proliferative effect, can inhibit cancer cell growth and proliferation of a variety of liver myofibroblast and abnormal proliferation of cells inhibited.Fibroblast-like synoviocytes hyperplasia tumors with similar characteristics, confirmed that resveratrol may inhibit the adoption of similar mechanisms in rheumatoid arthritis over the proliferation of fibroblast-like synoviocytes research results have been achieved, still need further clinical trials of animal confirmed.In addition, resveratrol as a gene therapy for rheumatoid arthritis drug's potential has yet to be confirmed.Objectives: Explore the different doses of resveratrol on collagen-induced arthritis(CIA)in rats with rheumatoid arthritis the therapeutic effect, to analyze the dose and the relationship between therapeutic effects and to explore its JAK - STAT signaling pathway role.Methods: Experimental use of bovine typeⅡc ollagen multi-point subcutaneous injection method to establish collagen-induced arthritis (CIA) model. The Wistar rats were randomly divided into two groups: normal control group(Control group) and model group(CIA group). The CIA group were immunized with the emulsifying solution of typeⅡcollagen acetic acid solution with Freund's incomplete adjuvant (FIA) spine along the center line near the back of rat skin by Multi-point subcutaneous injection, and received a booster injection of this emulsion by intraperitoneal injection 21 days later.The control group was injected contour of normal saline at the same time.Collected blood samples, using ELISA method determin the CIA group serum anti-collagenⅡantibody levels, as arthritis model success indicators. Observe the extent of joint swelling, skin temperature, subcutaneous nodules, erythema, etc. and to conduct joint clinical score.Rats arthritis model established successfully and arthritis index more than 2 points were randomly divided into collagen-induced arthritis (CIA) model group, resveratrol in low, middle and high dose group and the methotrexate group .They were given normal saline 1 mL /d (Control group, CIA group), resveratrol 2.5 mg/ ( kg·d),5 mg/ ( kg·d),10 mg/ ( kg·d), methotrexate 2.5 mg/ ( kg·w) by intragastric administration, then all the rats were sacrificed after 30 days, carried out histopathological score and get the knee joint synovial tissues at the same time. HE staining of tissue pathological changes in synovial membrane. Use Immunohistochemical(IHC) method and Western Blot assay to detect p-STAT1, p-STAT3 changes of different doses of resveratrol group. Using SPSS 13.0 statistical software for statistical analysis of data.Results:1. ELISA assay of anti-collagenⅡantibody results showed: Model group of anti-typeⅡcollagen antibody positive rate was significantly higher than the normal control group(P < 0.01).2. Body weight and arthritis index: CIA group, the rapid development of arthritis, arthritis index was significantly increased(P < 0.01), weight loss(P < 0.01); resveratrol low, middle and high dose group rats weight significantly heavier than the CIA group(P < 0.01), joint swelling reduced significantly lower than the CIA group(P < 0.01), and with the dose increase the effect of the more obvious(Correlation coefficient r valueP < 0.01) that high-dose group and the methotrexate group fairly. 3. Joint Histopathological score: Normal control group of synovial lining thickness of 1 ~ 2 layers of cells arranged neatly, no inflammatory cell infiltration and vascular proliferation, smooth articular cartilage damage; CIA group of organizations have different degree of synovial hyperplasia, thickening of lining layer, large quantities of synovial inflammatory cell infiltration, vascular expansion, the increase in the number, there are typical pannus formation and cartilage erosion of the growth of cartilage tissue in part by damage; Resveratrol low dose group Synovium moderate hyperplasia and inflammatory cell infiltration, and pannus formation and cartilage damage to a small number of pathological score with the CIA group has improved; Resveratrol middle dose group can be seen in synovial tissues moderate hyperplasia, a small amount of inflammatory cell infiltration, no significant damage to cartilage and bone tissue, with the CIA model group has significantly improved; Resveratrol high dose group:Only mild synovial hyperplasia, cell morphology rules, a small amount of inflammatory cell infiltration, non-typical pannus formation, cartilage surface, no cartilage damage and bone erosion, its pathology score with the methotrexate group fairly(P < 0.05).4. Immunohistochemistry results: Synovial p-STAT1, p-STAT3 expression was dark brown. Model group p-STAT1, p-STAT3 positive area compared with the control group significantly increased, the difference has statistical significance (P<0.01). Resveratrol low, middle and high dose group p-STAT1, p-STAT3 expression compared with the model group for the weak, but with higher doses of weaker expression(P<0.01,r= -0.912,-0.948, P < 0.01).5. Western Blot results: Normal control group of rats Synovium p-STAT1 and p-STAT3 free expression; while the CIA model group than the existence of a clear p-STAT1 and p-STAT3 positive expression strip; resveratrol low, middle and high dose group may inhibited to some extent, STAT1, STAT3 activation, and increased with the dose of application, such inhibition becomes even more evident.Conclusion: Resveratrol can effectively alleviate the symptoms of arthritis in rats and histopathological damage, and its dose-dependent effects exist, and can inhibit the excessive activation of STAT.
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