重组人内抑素对佐剂关节炎大鼠血清中肿瘤坏死因子-a、白细胞介素-6和瘦素表达水平的影响

目的研究重组人内抑素(endostatin,ES)对大鼠佐剂关节炎(AA)血清中TNF-a(肿瘤坏死因子-a)IL-6(白细胞介素-6)以及Leptin(瘦素)表达水平的影响,以探讨ES对AA的治疗作用。方法给大鼠右后足跖部皮内注射完全弗氏佐剂(CFA)建立AA模型。在致炎后第10天,大鼠继发性关节炎出现,开始在治疗组AA大鼠皮下注射内抑素2.5 mg/kg,连续7 d。直至第24天大鼠足爪肿胀度的抑制有显著性时,用放免法(RIA)测定大鼠血清中TNF-aI、L-6及Leptin的表达水平。结果治疗组AA大鼠血清中TNF-aI、L-6、Leptin水平低于造模组,血清中Leptin的表达水平与TNF-aI、L-6呈显著正相关。结论重组人内抑素对大鼠佐剂关节炎的继发炎症有明显抑制作用。治疗组血清中Leptin的表达水平与TNF-aI、L-6呈显著正相关。     

佐剂关节炎大鼠心功能变化与细胞因子、调节T细胞和Foxp3表达的相关性

目的:观察佐剂性关节炎(adjuvant arthritis,AA)大鼠足跖肿胀度(E)、关节炎指数(AI)、心功能、细胞因子、调节T细胞及Foxp3的表达,探讨细胞因子、转录因子Foxp3与调节T细胞(Treg)在AA大鼠心功能改变中的作用机制.方法:24只Wistar雄性大鼠随机分为正常组和模型组(Model组)各...     

Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis.

Prostaglandins formed by the cyclooxygenase (COX) enzymes are important mediators of inflammation in arthritis. The contribution of the inducible COX-2 enzyme to inflammation in rat adjuvant arthritis was evaluated by characterization of COX-2 expression in normal and arthritic paws and by pharmacological inhibition of COX-2 activity. The injection of adjuvant induced a marked edema of the hind footpads with coincident local production of PGE2. PG production was associated with upregulation of COX-2 mRNA and protein in the affected paws. In contrast, the level of COX-1 mRNA was unaffected by adjuvant injection. TNF-alpha and IL-6 mRNAs were also increased in the inflamed paws as was IL-6 protein in the serum. Therapeutic administration of a selective COX-2 inhibitor, SC-58125, rapidly reversed paw edema and reduced the level of PGE2 in paw tissue to baseline. Interestingly, treatment with the COX-2 inhibitor also reduced the expression of COX-2 mRNA and protein in the paw. Serum IL-6 and paw IL-6 mRNA levels were also reduced to near normal levels by SC-58125. Furthermore, inhibition of COX-2 resulted in a reduction of the inflammatory cell infiltrate and decreased inflammation of the synovium. Notably, the antiinflammatory effects of SC-58125 were indistinguishable from the effects observed for indomethacin. These results suggest that COX-2 plays a prominent role in the inflammation associated with adjuvant arthritis and that COX-2 derived PGs upregulate COX-2 and IL-6 expression at inflammatory sites.     

Evaluation of therapeutic potential of ivermectin against complete Freund's adjuvant-induced arthritis in rats: Involvement of inflammatory mediators

Rheumatoid arthritis is a chronic systemic inflammatory disease with genetic manifestations. According to recently published case reports, patients taking corticosteroid medication for the management of rheumatoid arthritis develop strongloidiasis and are at high risk of developing associated infections. This study explored the antiarthritic role of ivermectin, a drug used in the treatment of strongyloides and to compare its results with dexamethasone. Thirty-two male Wistar rats were randomly divided into four groups: control, diseased, dexamethasone, and ivermectin groups. Rheumatoid arthritis in all rats except the control group was induced by using complete Freund's adjuvant. After 7 days of rheumatoid arthritis induction, animals were treated with dexamethasone 5 mg/kg and ivermectin 6 mg/kg. Body weight, visual arthritic score, total leukocyte count, differential leukocyte count, proinflammatory genes, and histopathological findings were used to assess the effects of ivermectin on rheumatoid arthritis. Treatment with ivermectin showed a significant reduction in inflammatory cells levels, body weight, and visual arthritic score, indicating an improvement in the degree of inflammation as compared with the diseased group. Treatment with ivermectin and dexamethasone significantly reduced the augmentation in the mRNA expression levels of IL-17, TLR-2, TNF, and NF-κB as a result of arthritic development. Ivermectin treatment also showed a significant reduction in the severity of inflammation and destruction of joints and showed comparable effects to dexamethasone, a corticosteroid used for the treatment of rheumatoid arthritis. Ivermectin has significant antiarthritic properties and can be a novel treatment agent for the management of rheumatoid arthritis patients suffering from strongyloidiasis.     

Synergy between adjuvant arthritis and collagen-induced arthritis in rats

Adjuvant arthritis (AA) in rats is susceptible to cell-mediated passive transfer. Collagen-induced arthritis (CIA) in rats is susceptible to passive transfer with antibody to type II collagen. We report here the development of strikingly severe arthritis in Lewis rats as the result of synergy between passively transferred antibody to type II collagen from rats with CIA and concanavalin A (Con A)-stimulated lymph node or spleen cells from syngeneic rats with AA. Similar synergy was seen in rats with AA given anticollagen antibody, in rats with CIA given Con A-stimulated adjuvant spleen cells, and in rats actively immunized with CII and complete Freund's adjuvant. The synergistic process caused a very severe polyarthritis, characterized by marked swelling and erythema in all the joints of the distal extremities, with histologic and radiographic evidence of early, extensive erosion of articular cartilage. Synergy was apparent if the lymphoid cells from AA rats were given up to 1 mo after a single injection of anticollagen antibody. No synergy was seen when normal rat immunoglobulin or anti-ovalbumin antibody was substituted for anticollagen antibody, when Con A-stimulated lymphoid cells from normal rats or donors with CIA were used, or when Con A-stimulated AA lymphoid cells were irradiated before transfer. Synergy between separate immune effector mechanisms may represent a general phenomenon in the pathogenesis of inflammatory joint disease.     

佐剂关节炎大鼠血小板参数和细胞因子的变化及其相关性研究

目的观察佐剂关节炎(adjuvant arthritis,AA)大鼠血小板参数(血小板计数PLT、血小板压积PCT、血小板平均体积MPV、血小板分布宽度PDW)、细胞因子(IL-1β、TNF-α、IL-10)的变化并对其行相关性分析。方法将16只SD雄性大鼠随机分为健康对照组、模型组,每组8只,用弗氏完全佐剂(Freund's com-plete adjuvant,CFA)向模型组大鼠右后足跖皮内注射0.1ml诱发大鼠产生关节炎,观察两组大鼠血小板参数(PLT、PCT、PDW、MPV)和细胞因子(IL-1β、TNF-α、IL-10)的变化。结果与健康对照组相比,模型组大鼠血小板参数PLT、PCT、IL-1β、TNF-α显著升高,IL-10降低(P<0.05或P<0.01)。AA大鼠的血小板参数PLT、PCT与IL-1β、TNF-α、足跖肿胀度、关节炎指数呈正相关,与IL-10呈负相关(P<0.01或P<0.05)。结论佐剂关节炎大鼠PLT、PCT是升高的,且与IL-1β、TNF-α、IL-10、足跖肿胀度、关节炎指数具有正相关性;升高机制可能与致炎因子IL-1β和TNF-α升高,抑炎因子IL-10下降有关。     

雷公藤多甙对佐剂性关节炎模型大鼠踝关节相关指标的影响

背景:类风湿性关节炎是常见的自身免疫性疾病。近年来雷公藤多甙广泛应用于类风湿性关节炎治疗,其治疗过程中对关节滑膜炎症的影响及对类风湿性关节炎的预防作用有待研究。目的:观察雷公藤多甙对佐剂性关节炎模型大鼠踝关节相关指标的影响。设计:随机对照动物实验。单位:四川大学基础医学与法医学院组织胚胎学与神经生物学教研室。材料:选用20只健康清洁级雌性SD大鼠,体质量(200±15)g,鼠龄二三个月,由四川大学实验动物中心提供。氟氏完全佐剂为Sigma公司产品,雷公藤多甙为湖南株州制药三厂产品(批准文号:湘卫药准字(2005)第055172号。剂量:10mg/片)。方法:实验于2004-05/2006-03在四川大学组织胚胎学和神经生物学教研室完成。抽签法随机将大鼠分为正常组、模型组、预防组及治疗组,每组5只。正常组不造模,不给药物治疗;模型组于实验开始后,分别在各个大鼠左后足垫部皮下注射氟氏完全佐剂0.2mL,不给药物治疗;预防组造模方法同模型组,造模后第7天开始灌胃给予雷公藤多甙,用药剂量以大鼠体表面积换算公式计算,1次/d,每次30mg/kg,共7d;治疗组造模方法同模型组,造模后第19天开始灌胃给予雷公藤多甙,方式和疗程同预防组。①采用足跖容积法于造模前,造模后2,10,15,19,22,26d不同时间点观察记录大鼠原发侧与继发侧关节后肢肿胀程度。②根据其余未注射的3只肢体的病变程度及指间趾间关节是否发炎,评价大鼠关节炎指数(0分:肿胀度≤5%;1分:肿胀≤15%;2分:15%<肿胀≤30%;3分:30%<严重肿胀≤60%;4分:肿胀>60%),把每个关节的得分累计起来,即为每只大鼠的关节炎指数。③造模后28d取材,将大鼠灌注固定后,取完整踝关节切片,苏木精-伊红染色后观察大鼠踝关节滑膜组织的改变。主要观察指标:各组大鼠关节肿胀程度、关节炎指数及踝关节滑膜组织学观察。结果:大鼠20只均进入结果分析。①造模2d后,除正常组外,其他各组大鼠原发侧关节均出现明显肿胀,造模2～26d各时间点大鼠足跖容积均大于正常组(t=2.315～3.041,P<0.05);预防组大鼠造模后10,15,19,22,26d原发侧足跖容积小于模型组(t=2.064～2.683,P<0.05);治疗组大鼠造模后22,26d原发侧足跖容积小于模型组(t=2.112～2.578,P<0.05)。造模15d后,模型组和治疗组大鼠继发侧足跖容积均大于正常组(t=2.201～2.546,P<0.05),预防组大鼠造模15,19,22,26d继发侧足跖容积小于模型组(t=2.373～2.425,P<0.05);治疗组大鼠造模26d继发侧足跖容积小于模型组(P<0.05)。②造模14d,模型组大鼠关节炎指数为(8.3±2.0)分,预防组为(0.4±0.95)分,预防组较模型组明显降低(t=2.64,P<0.05);造模26天,治疗组为(7.3±1.3)分,明显低于模型组(11.2±0.9)分(t=3.26,P<0.05)。③正常组大鼠踝关节腔内干净,关节软骨表面光滑,软骨无退行性变,滑膜组织无增生。模型组大鼠原发侧踝关节滑膜增生,滑膜细胞数量增多,体积增大,排列为多层;滑膜下组织水肿,充血,炎性细胞浸润。模型组继发侧继发性病变表现为滑膜增生,踝关节滑膜下组织水肿。预防组原发侧踝关节滑膜与模型组比较,滑膜炎症反应减弱,增生程度减轻。继发侧踝关节滑膜未见明显增生。治疗组原发侧及继发侧踝关节滑膜与模型组比较,滑膜组织增生减少,炎症反应减轻。结论:雷公藤多甙能显著减轻大鼠足跖关节肿胀度,关节炎症指数,减轻踝关节滑膜病理改变,且能预防继发性病变的出现。     

Modeling corticosteroid effects in a rat model of rheumatoid arthritis II: mechanistic pharmacodynamic model for dexamethasone effects in Lewis rats with collagen-induced arthritis

A mechanism-based model for pharmacodynamic effects of dexamethasone (DEX) was incorporated into our model for arthritis disease progression in the rat to aid in identification of the primary factors responsible for edema and bone loss. Collagen-induced arthritis was produced in male Lewis rats after injection of type II porcine collagen. DEX was given subcutaneously in single doses of 0.225 or 2.25 mg/kg or 7-day multiple doses of 0.045 or 0.225 mg/kg at 21 days postdisease induction. Effects on disease progression were measured by paw swelling, bone mineral density (BMD), body weights, plasma corticosterone (CST), and tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and glucocorticoid receptor (GR) mRNA expression in paw tissue. Lumbar and femur BMD was determined by PIXImus II dual-energy X-ray absorptiometry. Plasma CST was assayed by high-performance liquid chromatography. Cytokine and GR mRNA were assayed by quantitative real-time polymerase chain reaction. Indirect response models, drug interaction models, transduction processes, and the fifth-generation model of corticosteroid dynamics were integrated and applied using S-ADAPT software to describe how dexamethasone binding to GR can regulate diverse processes. Cytokine mRNA, GR mRNA, plasma CST, and paw edema were suppressed after DEX administration. TNF-alpha mRNA expression and BMD seemed to increase immediately after dosing but were ultimately reduced. Model parameters indicated that IL-6 and IL-1beta were most sensitive to inhibition by DEX. TNF-alpha seemed to primarily influence edema, whereas IL-6 contributed the most to bone loss. Lower doses of corticosteroids may be sufficient to suppress the cytokines most relevant to bone erosion.     

脊髓背角核因子κB表达与佐剂关节炎大鼠的痛觉过敏

背景:核因子kB作为炎症反应的启动因子,可刺激损伤部位或炎症局部基因的转录,促进炎性因子的产生,导致疼痛的发生,但其在参与慢性炎性疼痛脊髓机制中的作用目前研究甚少.目的:制备稳定的油包水剂型完全弗式佐剂单关节炎大鼠模型,并对大鼠疼痛行为学痛觉过敏及脊髓背角核因子KB表达进行观察和探讨.方法:24只大鼠被随机分为假手术对照组、完全弗氏佐剂组,每组12只.大鼠右踝关节腔内注射含灭活结核杆菌的黏稠油包水型完全弗式佐剂,假手术组注射50 μL生理盐水至大鼠右踝关节腔内,观察大鼠完全弗式佐剂注射前2 d,注射后4,7,14,21,28 d的机械压痛、辐射热痛、关节肿胀周径(内外踝下缘周长)及脊髓背角核因子kB表达的变化.结果与结论:①注射3 h,大鼠右踝关节出现明显肿胀,但局部红、热不明显,注射24 h,右踝关节红肿显著且波及足跖面,并持续4周.②注射4 d～4周,大鼠右踝关节周径在较对侧及注射前显著增加(P＜0.01).⑨与注射前及假手术组相比,完全弗氏佐剂组机械压痛阈值在注射后4 d明显下降,注射后21 d降至最低值(P均＜ 0.01);注射4 d,与注射前相比,完全弗氏佐剂组大鼠息侧辐射热痛阈值明显下降,7 d降至最低点后逐渐稳定,并持续4周(P均＜0.01).④完全弗氏佐剂组大鼠患侧腰段脊髓背角Ⅰ～Ⅵ层核因子KB表达明显高于假手术组(P＜0.01).证实关节腔内注射油包水型完全弗式佐剂可获得稳定的单关节炎疼痛模型,大鼠关节致炎后出现明显的辐射热及压痛痛觉过敏,且持续时间长,痛敏阈值稳定,脊髓背角Ⅰ～Ⅵ层核因子kB表达明显升高.     

Intra-articular IL-4 gene therapy in arthritis: anti-inflammatory effect and enhanced th2activity

Gene therapy has been explored as a potential method for treating chronic inflammatory diseases such as rheumatoid arthritis. To determine the efficacy of intra-articular IL-4 gene therapy in an animal model of arthritis using a retroviral vector, a retrovirus encoding rat IL-4 (DA-IL-4) was engineered, purified and concentrated to high titer (>/=109 CFU/ml). Infectivity and expression levels were demonstrated in vitro using cultured fibroblast-like synoviocytes. Efficacy was evaluated in the rat adjuvant arthritis model. DA-IL-4 or DA-beta-gal retrovirus was injected into the intra-articular joint space of the right ankle on day 12 after immunization. Three days after joint injection, the injected paw contained increased levels of IL-4 compared with control or with the contralateral uninjected paw, demonstrating successful transgene expression. Surprisingly, 8 days after treatment IL-4 levels continued to increase in the injected and contralateral paw compared with DA-beta-gal-treated animals. Serum IL-4 levels were also elevated in DA-IL-4-treated rats. RT-PCR studies demonstrated that the transgene was expressed in the injected ankle but not in the contralateral joint. IL-4 gene therapy resulted in a significant reduction in paw swelling and decreased radiographic evidence of bone destruction. This is the first demonstration of successful intra-articular retroviral gene treatment using a therapeutic gene. In addition to its anti-inflammatory effect, this study supports the potential application of intra-articular gene therapy as a method for enhancing systemic Th2 function.     

复方丹参注射液对关节炎模型大鼠滑膜细胞白细胞介素1β mRNA表达的影响

目的研究复方丹参对Ⅱ型胶原蛋白诱导性大鼠关节炎模型(CIA)滑膜细胞白细胞介素1β(IL-1β)mRNA表达的影响.方法用Ⅱ型胶原蛋白诱导大鼠关节炎模型,以反转录-多聚酶链反应(RT-PCR)半定量法测定模型大鼠滑膜细胞IL-1βmRNA的表达.结果氯化钠注射液组、地塞米松组、小剂量丹参组IL-1βmRNA的表达均高于大剂量丹参组,差异有非常显著性意义(P＜0.01).结论复方丹参治疗类风湿性关节炎的机制可能与下调滑膜细胞IL-1βmRNA表达的水平有关.     

Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy

Peripheral hypersensitivity (hyperalgesia and allodynia) are common phenomena both in inflammatory and in neuropathic pain conditions. Several rat models of mononeuropathy (Bennett, Seltzer and Gazelius models) display such symptoms following partial injury to the sciatic nerve. Using immunohistochemistry and behavioral tests, we investigated inflammatory cell and cytokine responses in the sciatic nerve 14 days after injury created in these different models as well as after axotomy. Tactile hypersensitivity ('allodynia') was present in all Gazelius model rats whereas only 38 and 29% of the Bennett and Seltzer models, respectively, displayed this sign of neuropathy. The inflammatory reactions in rats with and without tactile allodynia were compared. Monocytes/macrophages (ED-1), natural killer cells, T lymphocytes, and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), were significantly upregulated in all nerve injured rats in comparison to sham-operated controls. Interestingly, ED-1-, TNF-alpha- and IL-6-positive cells increased more markedly in allodynic Bennett and Seltzer rats than in non-allodynic ones. The magnitude of the inflammatory response does not seem to relate to the extent of damage to the nerve fibers because axotomized rats displayed much lower upregulation. Our findings indicate that the considerable increase in monocytes/macrophages induced by a nerve injury results in a very high release of IL-6 and TNF-alpha. This may relate to the generation of tactile allodynia/hyperalgesia, since there was a clear correlation between the number of ED-1 and IL-6-positive cells and the degree of allodynia. It is possible that measures to reduce monocyte/macrophage recruitment and the release of pro-inflammatory interleukins after nerve damage could influence the development of neuropathic pain.     

甲基强的松龙肾囊内注射对原发性肾病综合征患者IL-18，IL-6和TNF—α的影响

【目的】探讨炎症因子白介素18（IL-18）、肿瘤坏死因子α（TNF—α）及白介素-6（IL-6）在肾脂肪囊（肾囊）内注射甲基强的松龙（MP）治疗肾病综合征（PNS）中可能的作用机制。【方法】154例PNS患者在B超引导下向每侧肾囊内注射MP40mg治疗,每周2次,共10次。观察治疗前及治疗2、8周后24h尿蛋白定量及白蛋白的水平。以及血、尿中IL-18、TNF—α及IL-6等指标的变化。【结果】54例患者中44例（81．4％）,尿蛋白明显减少或转阴;治疗前血、尿IL-18、TNF-α及IL-6含量明显增高。治疗8周后患者血、尿TNF-α及IL-6的水平明显下降,与蛋白尿的下降呈正相关;同时伴有尿IL-18的下降,而血IL—18无明显变化。【结论】肾囊内注射MP治疗PNS具有一定的疗效。抑制肾脏局部IL-18以及全身的TNF-α及IL-6介导的炎性损伤可能为其重要的作用机制。     

Inhibition of IL-6 signaling: A novel therapeutic approach to treating spinal cord injury pain

To characterize the contribution of interleukin-6 (IL-6) to spinal cord injury pain (SCIP), we employed a clinically relevant rat contusion model of SCIP. Using Western blots, we measured IL-6 levels in lumbar segments (L1-L5), at the lesion site (T10), and in the corresponding lumbar and thoracic dorsal root ganglia (DRG) in 2 groups of similarly injured rats: (a) SCI rats that developed hind-limb mechanical allodynia (SCIP), and (b) SCI rats that did not develop SCIP. Only in SCIP rats did we find significantly increased IL-6 levels. Immunocytochemistry showed elevated IL-6 predominantly in reactive astrocytes. Our data also showed that increased production of IL-6 in hyperreactive astrocytes in SCIP rats may explain still-poorly understood astrocytic contribution to SCIP. To test the hypothesis that IL-6 contributes to mechanical allodynia, we treated SCIP rats with neutralizing IL-6 receptor antibody (IL-6-R Ab), and found that one systemic injection abolished allodynia and associated weight loss; in contrast to gabapentin, the analgesic effect lasted for at least 2 weeks after the injection, despite the shorter presence of the Ab in the circulation. We also showed that IL-6-R Ab partially reversed SCI-induced decreases in the protein levels of the glutamate transporter GLT-1 12 hours and 8 days after Ab injection, which may explain the lasting analgesic effect of the Ab in SCIP rats. A link between reactive astrocytes IL-6-GLT-1 has not been previously shown. Given that the humanized IL-6-R Ab tocilizumab is Food and Drug Administration-approved for rheumatoid arthritis, we are proposing tocilizumab as a novel and potentially effective treatment for SCIP.     

Effects of polyenylphosphatidylcholine on cytokines,nitrite/nitrate levels,antioxidant activity and lipid peroxidation in rats with sepsis

OBJECTIVES: To determine the effect of pretreatment with polyenylphosphatidylcholine (lecithin, PPC) on plasma levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10, total nitrite/nitrate (NOx), and tissue levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in septic rats. DESIGN: Prospective, randomized, controlled animal study. SETTING: University laboratory. SUBJECTS: Forty-five Spraque-Dawley rats were divided into three groups: group C, sham-operated; group S, sepsis; and group P, sepsis pretreated with PPC. INTERVENTIONS: Rats were made septic by cecal ligation and puncture (CLP). Group P rats were treated with PPC (100 mg/day orally) for 10 days before sepsis. Twenty-four hours later CLP, plasma concentrations of TNF-alpha, IL-6 and IL-10 and plasma levels of NOx were measured. SOD and MDA were determined in liver, lung and heart homogenates. MEASUREMENTS AND MAIN RESULTS: All rats in group P survived during the 24-h observation time after CLP, whereas survival rate in group S was 66.7% (10/15; P<0.05). PPC significantly reduced plasma levels of TNF-alpha (P=0.006), IL-6 (P=0.007), IL-10 (P=0.016), NOx (P<0.001), and tissue levels of MDA (P<0.001) in group P with respect to in group S. Tissue levels of SOD significantly increased in group P when compared with group S (P<0.001). CONCLUSIONS: These results show that PPC pretreatment exerts cumulative effects in decreasing the levels of cytokines, NOx, and tissue MDA concentrations, with a concomitant increase in survival in septic rats. Lecithin therapy may be a useful adjuvant therapy in controlling of the excessive production of the inflammatory cytokines in patients with severe sepsis. DESCRIPTOR: SIRS/sepsis, experimental studies.     

Coexpression of phosphotyrosine-containing proteins, platelet-derived growth factor-B, and fibroblast growth factor-1 in situ in synovial tissues of patients with rheumatoid arthritis and Lewis rats with adjuvant or streptococcal cell wall arthritis.

Fibroblast growth factor (FGF)-1 and PDGF-B-like factors have been implicated in the pathobiology of RA and animal models of this disease. Since the receptors for FGF-1 and PDGF are tyrosine kinases, we examined the expression of tyrosine phosphorylated proteins (phosphotyrosine, P-Tyr) in synovial tissues from patients with RA and osteoarthritis (OA), and rats with streptococcal cell wall (SCW) and adjuvant arthritis (AA). Synovia from patients with RA and LEW/N rats with SCW and AA arthritis, in contrast to controls, stained intensely with anti-P-Tyr antibody. The staining colocalized with PDGF-B and FGF-1 staining. Comparative immunoblot analysis showed markedly enhanced expression of a 45-kD P-Tyr protein in the inflamed synovia. Treatment with physiological concentrations of dexamethasone suppressed both arthritis and P-Tyr expression in AA. P-Tyr was only transiently expressed in athymic nude Lewis rats and was not detected in relatively arthritis-resistant F344/N rats. These data suggest that (a) FGF-1 and PDGF-B-like factors are upregulated and may induce tyrosine phosphorylation of proteins in vivo in inflammatory joint diseases, (b) persistent high level P-Tyr expression is T lymphocyte dependent, correlates with disease severity, and is strain dependent in rats, (c) corticosteroids, in physiological concentrations, downregulate P-Tyr expression in these lesions.     

Cytokine profiles during carrageenan-induced inflammatory hyperalgesia in rat muscle and hind paw.

It is not known if a cytokine cascade develops during muscle inflammation and whether cytokines contribute to muscle inflammatory pain. We measured plasma and tissue cytokine concentrations, and behavioral responses to noxious mechanical stimuli, after inducing inflammation in the gastrocnemius muscle and the hind paw of rats. Tissue and plasma samples were taken 3, 6, or 24 h after carrageenan or saline injection into one of the 2 sites. Tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and cytokine-induced neutrophil chemoattractant 1 (CINC-1) concentrations were measured. Hyperalgesia was present 3 h after carrageenan injection into the hind paw and muscle. The TNF-alpha was elevated significantly in the inflamed hind paw tissue (P < .001) but not in inflamed muscle tissue. IL-1beta was elevated 6 h after carrageenan injection in the hind paw tissue but only 24 h in the muscle tissue (P < .001). The IL-6 was elevated 3 h after injection in the hind paw tissue but only after 6 h in the muscle tissue (P < .01). The CINC-1 in plasma, muscle, and hind paw was elevated from 3 h to 24 h after carrageenan injection (P < .01). The release of IL-1beta and IL-6, known to mediate hyperalgesia elsewhere, is delayed in muscle inflammation compared with cutaneous inflammation, whereas TNF-alpha is not elevated during muscle inflammation. PERSPECTIVE: The quality and mechanisms of muscle pain are different from that of cutaneous pain. So too is the pattern of cytokine release during inflammation. Inhibiting TNF-alpha is unlikely to be effective in managing inflammatory muscle pain, but other cytokines, notably IL-1beta and CINC-1, may prove useful therapeutic targets.     

芍药苷对胶原诱导型关节炎模型的治疗作用及机制

目的 探讨芍药苷（paeoniflorin）对胶原诱导型大鼠关节炎（CIA）滑膜增殖和治疗的影响.方法 采用完全弗氏佐剂和Ⅱ型胶原诱导大鼠CIA模型,计数方法测定多发性关节炎指数（AJ）,称重法比较大鼠的体重变化,HE染色法光镜观察关节病理形态学变化,酶联免疫吸附试验（ELISA）检测巨噬细胞分泌的白细胞介素-6（IL-6）、肿瘤坏死因子（TNF）-α,免疫组化检测滑膜细胞凋亡水平.结果 芍药苷对CIA大鼠的关节炎指数和关节病理评分都有改善,芍药苷组的各炎症因子的表达较模型组降低,芍药苷治疗后滑膜细胞凋亡较对照组增加,差异均有统计学意义（P＜0.05）.结论 芍药苷可以增加CIA大鼠关节炎滑膜细胞凋亡,降低CIA大鼠的关节炎指数和炎症因子含量.     

Immunomodulation and Antioxidant Effects of Anthocyanins from Cherries on Adjuvant-Induced Arthritis in Rats

Objective

The effects of anthocyanins from cherries on adjuvant-induced arthritis (AIA) in rats were investigated by measuring the levels of tumour necrosis factor-α (TNFα), interleukin-6 (IL-6), prostaglandin E₂ (PGE₂) and by measuring the antioxidant effects.

Materials and Methods

Arthritis was induced intradermally by injection with 0.1mL of complete Freund’s adjuvant into the right hind footpad in male Sprague Dawley® (SD) rats. Anthocyanins at 300, 150 and 75 mg/kg bodyweight were administered orally to the treated rats once daily for 28 days after the injection. The swellings in the left hind paws were assayed for arthritic index. TNFα, IL-6 in serum and PGE₂ in paws were assayed by radioimmunoassay, and the antioxidant effects were assayed by testing Superoxide dismutase (SOD) and malondialdehyde (MDA) in serum.

Results

Anthocyanins could significantly reduce the paw swelling from day 15 to day 28 after the injection, decrease the levels of TNFα, IL-6 and MDA in serum and PGE₂ in paws, and increase activity of SOD in serum on day 28 after the injection.

Conclusions

The anthocyanins could protect against AIA in SD rats, and the mechanism works partly by regulating the inflammatory cytokines and improving the antioxidative status of AIA.