El-Sherbiny Mohamed, Atef Hoda, Eladl Mohamed Ahmed, Mohamed Abdelaty Shawky, El-Shafey Mohamed, Ali Howaida S, Zaitone Sawsan A, Alomar Suliman Y, Alqahtani Saeed Awad M, Aloyouni Sheka Yagub, Attia Mohammed A
Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia.
Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Front Pharmacol. 2021 Apr 23;12:631216. doi: 10.3389/fphar.2021.631216. eCollection 2021.
Recently, the therapeutic importance of the anti-rheumatic drug, leflunomide, has been increased after the involvement of leflunomide in treating other autoimmune diseases and its promising role in retarding human malignancies. Few studies have focused on the safety in human or animals without clear outlining of the pathologic features on target organs. One clinical study related leflunomide with significant pulmonary complications in predisposed individuals. The current study examined the dose-dependent lung injury produced by leflunomide in healthy mice. Albino mice were allocated into four different groups. Group (1): Vehicle control group, Group (2-4): mice received leflunomide (2.5, 5 or 10 mg/kg), respectively, for 8 weeks and then lungs were dissected from the mice for histopathological examination and fibrosis evaluation (Masson's trichrome staining and α-smooth muscle actin immunohistochemistry). Enzyme linked immunosorbent assay was used to assess the vimentin and other inflammatory factors in the lung homogenate whereas Western blot analysis was employed to assess α-smooth muscle actin, vimentin and collagen 1. Results indicated that leflunomide induced dose-dependent pulmonary injury and the high dose and increased the vimentin, inflammatory markers (NLRP3 and interlukin-1β). Histologic examination showed distorted architecture, marked inflammatory cells infiltrate and increase collagen content. The findings were supported by Western blotting and the immunohistochemical study which showed greater pulmonary α-smooth muscle actin and vimentin content. In conclusion, the current results highlighted that leflunomide produced dose-dependent pulmonary toxicities that requires further investigation of the nature of injury.
最近，抗风湿药物来氟米特在治疗其他自身免疫性疾病中的应用及其在延缓人类恶性肿瘤方面的潜在作用，使其治疗重要性有所提高。很少有研究关注其在人类或动物中的安全性，且未明确勾勒出靶器官的病理特征。一项临床研究表明，来氟米特会使易感个体出现严重的肺部并发症。本研究检测了来氟米特在健康小鼠中产生的剂量依赖性肺损伤。将白化小鼠分为四个不同组。第1组：溶剂对照组；第2 - 4组：小鼠分别接受来氟米特（2.5、5或10毫克/千克），持续8周，然后从小鼠体内取出肺脏进行组织病理学检查和纤维化评估（Masson三色染色和α - 平滑肌肌动蛋白免疫组织化学）。采用酶联免疫吸附测定法评估肺匀浆中的波形蛋白和其他炎症因子，同时采用蛋白质印迹分析评估α - 平滑肌肌动蛋白、波形蛋白和胶原蛋白1。结果表明，来氟米特可诱导剂量依赖性肺损伤，高剂量会增加波形蛋白、炎症标志物（NLRP3和白细胞介素 - 1β）。组织学检查显示结构扭曲、明显的炎症细胞浸润和胶原蛋白含量增加。蛋白质印迹和免疫组织化学研究支持了这些发现，结果显示肺部α - 平滑肌肌动蛋白和波形蛋白含量更高。总之，目前的结果突出表明，来氟米特会产生剂量依赖性肺毒性，这需要对损伤的性质进行进一步研究。
