摘要
目的探讨阻断Janus激酶-信号转导子和转录活化子(JAK-STAT)信号通路对大鼠类风湿关节炎的治疗作用。方法2005年10月至2006年9月在中国医科大学实验动物中心将关节炎模型建立成功且关节炎指数大于2分的30只大鼠随机分为胶原诱导的关节炎(CIA)模型组,JAK-STAT信号通路特异性阻断剂(AG490)低、中、高剂量组及来氟米特组,另有6只大鼠为正常对照组。分别予以生理盐水1mL/d(对照组,CIA模型组)、AG4901、5、10mg/(kg.d)、来氟米特10mg/(kg.d)腹腔注射或灌胃,44d后处死。比较大鼠体重、关节炎指数、足趾容积、病理评分及p-STAT1、p-STAT3的变化情况。结果CIA模型组关节炎发展迅速,关节炎指数、足趾容积明显增高,p-STAT1、p-STAT3表达增多,体重减轻;AG490低剂量组大鼠体重较CIA模型组有所增加,关节肿胀减轻,在一定程度抑制了JAK-STAT的激活;AG490中剂量组在体重、关节炎指数、足趾容积、病理评分等方面均较CIA模型组有明显改善(P<0.05),其疗效与来氟米特相当,同时可明显抑制JAK-STAT通路的激活;AG490高剂量组病理评分改善程度优于来氟米特组。结论JAK激酶特异性阻断剂AG490可以明显抑制STAT的过度激活,有效地减轻大鼠关节炎症状及组织病理损害,其疗效存在剂量依赖性。
Objective To approach the effect of blocking the JAK-STAT signal pathway in the treatment of rat＇s rheumatoid arthritis. Methods Thirty-six arthritis rat models,which had arthritis index more than 2 scores, were built successfully by Department of Rheumatology and Immunology, the First Affiliated Hospital of China Medical University, and they were divided into model group one and two,low dose of AG490 group, middle dose of AG490 group, high dose of AG490 group and leflunomide group. Besides, 6 rats were treated as normal control group. And they were given normal sodium 1 mL,AG490 1,5,10 mg/（ kg · d）and leflunomide 10 mg/（ kg · d） by intraperitoneal injection or intragastric adminis- tration, then all the rats were sacrificed after 44 days. After that, compared the weight, arthritis index, the volume of toe, pathological score, and the change of p-STAT1, p-STAT3. Results The arthritis of model group developed rapidly, and the arthritis index, the volume of toe increased obviously, and the expression of p-STAT1 and p-STAT3 increased and the body weight decreased, all of which had significant meaning compared with that of control group. The body weights of rats in low dose group of AG490 were heavier than that of control group, the symptom of arthroeele in low dose group of AG490 was lighter than that of control group,and could inhibited the activation of JAK-STAT signal pathway in some degree,but the arthritis index numbers and the pathological score had no significant difference from that of model group. The body weights, arthritis index, the volume of toe and pathological score in middle dose group of AG490 improved obviously （P 〈 0. 05）. The therapeutic effect of AG490 was correspondent with that of leflunomide, and could also inhibit the activation of the signal pathway. Moreover, the high dose group of AG490 exerted effect earlier and the improving extent of pathological score was better than that of leflunomide group. Conclusion AGd.90 is the special blocking agent of JAK, which can inhibit the excess activating of STAT and lighten the symptom of rats＇ arthritis as well as decreased the pathological lesion of tissue and the therapeutic effect shows dose dependent.
出处
《中国实用内科杂志》
CAS
CSCD
北大核心
2007年第11期872-875,共4页
Chinese Journal of Practical Internal Medicine
