来氟米特是否诱导大鼠发生肺纤维化  

To investigate whether lefiunomide induces pulmonary fibrosis in rats

作　　者：张呈菊[1] 钱蓓丽[1] 蒋建强[1] 浦瑞麟[1] 叶义豪[1] 史民华[1] 杨琛懋[1] 殷承胜[1] 

机构地区：[1]上海医药工业研究院国家上海新药安全评价研究中心,上海201203

出　　处：《中国新药与临床杂志》2007年第7期481-486,共6页Chinese Journal of New Drugs and Clinical Remedies

摘　　要：目的:研究来氟米特是否诱导大鼠发生肺纤维化。方法:SD大鼠90只,随机分5组,每组18只。分别单次气管内给予生理盐水1.25 mL·kg^(-1)、来氟米特(2mg·kg^(-1),15mg·kg^(-1))、来氟米特杂质(0.02mg·kg^(-1))和博来霉素(5mg·kg^(-1)),给药后2和4wk收集出肺血液,检测其中丙二醛(MDA)和NO_2^-/NO_3^-的含量;给药后1、2和4wk,肺称重计算肺系数,用Masson三重染色和天狼猩红特殊染色,光镜和电镜检查肺组织的病理变化;免疫组织化学法检测肺组织中TGF-β1表达。结果:单次气管内给药后,与生理盐水组相比,来氟米特低、高剂量组出肺血液中MDA和NO_2^-/NO_3^-的含量无明显变化,而博来霉素组显著升高(均P<0.01)。与生理盐水组相比,来氟米特低、高剂量组大鼠肺系数无明显变化,而博来霉素组显著增大(P<0.01)。来氟米特给药组大鼠未发生肺纤维化毒性反应病理变化,而阳性对照博来霉素组出现典型的早期肺炎和后期肺纤维化的病理变化。结论:来氟米特未诱导大鼠发生肺纤维化的不良反应。AIM： To investigate whether leflunomide induces pulmonary fibrosis in rats. METHODS： Sprague-Dawley rats were given intratracheal single dose administration of leflunomide; 2 and 4 weeks later, out-flow pulmonary blood was collected with measurement of MDA and NO2^-/NO3^-; and at 1, 2 and 4 weeks, the lungs tissues were collected and weighted to calculate the lung coefficient. The lungs tissues were stained with Masson trichrome or special sirius red for grading the changes of pulmonary inflammation and fibrosis under light and electron microscopy. TGF-β1 expression in lung tissue was evaluated by immunohistochemistry. RESULTS： After single dose intratracheal administration of leflunomide compared with NS group, the contents of NO2^-/NO3^- and MDA in out-flow pulmonary blood revealed no significant changes, but that.of Blm group showed significant increase （P 〈 0.01） . Lef 1, Lef 2 groups compared with NS group, the lung coefficient revealed no significant changes, but Blm group showed significant increase （P 〈 0.01 ） . No pulmonary fibrosis was found in lefluniomide treated rats, but typical early pulmonary inflammation and later stage pulmonary fibrosis occurred in positive control, bleomycin treated rats. CONCLUSION： Leflunomide does not induce adverse reaction of pulmonary fibrosis in rats.

关 键 词：来氟米特 博来霉素 肺纤维化 

分 类 号：R971.1[医药卫生—药品] R563[医药卫生—药学]