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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。
Objective: To investigate whether leflunomide induced pulmonary fibrosis in rats. Methods: Ninety Sprague-Dawley rats were randomly divided into five groups (n = 18 each). A single intraperitoneal injection of saline (1.25 mL · kg -1), leflunomide (2 mg · kg -1, 15 mg · kg -1), leflunomide (0.02 mg · Kg -1 and bleomycin 5 mg · kg -1, respectively. Pulmonary blood was collected at 2 and 4 weeks after administration, and malondialdehyde (MDA) and NO 2 - / NO 3 - The lung coefficient was calculated by lung weighing at 1, 2 and 4wk after administration, the pathological changes of lung tissue were examined by Masson’s triple staining and Sirius red staining, the pathological changes of lung tissue were observed by light and electron microscopy, the expression of TGF -β1 expression. Results: After a single intratracheal instillation, there was no significant change in the content of MDA and NO 2 - / NO 3 - in the pulmonary blood of leflunomide-treated and high-dose groups compared with saline group, whereas bleomycin Group were significantly increased (all P <0.01). Compared with the saline group, the lung coefficient of leflunomide low and high dose groups had no significant change, while the bleomycin group increased significantly (P <0.01). In the leflunomide group, pathological changes of pulmonary fibrosis were not observed in the rats in the leflunomide group, while pathological changes of typical early and late pulmonary fibrosis occurred in the positive control bleomycin group. Conclusion: Leflunomide does not induce adverse reactions of pulmonary fibrosis in rats.