Treatment of experimental autoimmune uveoretinitis with atorvastatin and lovastatin
Treatment of experimental autoimmune uveoretinitis with atorvastatin and lovastatin
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DOI：
10.1016/j.exer.2006.11.011
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发表时间：
2007-03-01
影响因子：
3.4
通讯作者：
Kitahara, Kenji
中科院分区：
文献类型：
--
作者：
Kohno, Hideo;Sakai, Tsutomu;Kitahara, Kenji
他汀类药物是3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，被批准用于降低胆固醇，通常用于治疗动脉粥样硬化和冠状动脉疾病。他汀类药物也可能是有效的免疫调节剂，并可能有益于治疗自身免疫性疾病。本研究探讨了阿托伐他汀和洛伐他汀对实验性自身免疫性葡萄膜视网膜炎（EAU）的治疗作用。用牛S抗原（S-Ag）肽诱导刘易斯大鼠EAU。将阿托伐他汀混悬于0.5%甲基纤维素水溶液中，以10 mg/kg和1 mg/kg的低剂量经口给药。将洛伐他汀溶解于DMSO：PBS（1：1）中，并通过腹膜内（i. p.）以2 mg/kg的剂量注射。两种他汀类药物治疗均在临床发作后开始，每日一次，持续14天。每隔一天检查大鼠的EAU临床体征。免疫后第28天进行组织学评分和迟发型超敏反应（DTH）评价。光镜和共聚焦显微镜分别进行形态学和免疫组化检查。通过[3 H]胸苷掺入腹股沟淋巴结抗原刺激的T细胞来测量淋巴细胞增殖。72小时后，收集上清液并通过ELISA测定IFN-γ。阿托伐他汀（10 mg/kg）和洛伐他汀（2 mg/kg）治疗组的EAU临床和组织学评分均降低。阿托伐他汀和洛伐他汀治疗组均抑制了T细胞和巨噬细胞的侵袭以及Muller细胞的增殖。与溶剂处理组（对照组）相比，两组的DTH均受到显著抑制。淋巴细胞增殖试验表明，与对照组相比，在25 μ g/ml S-Ag肽存在下，两组的增殖均降低。与对照组相比，在用S-Ag肽（5 μ g/ml）刺激的淋巴结细胞的上清液中，在用阿托伐他汀或洛伐他汀处理的大鼠中分别观察到IFN-γ产生的77%或87%抑制。目前的研究结果表明，阿托伐他汀口服给药的临床发病后，在EAU的治疗效果，以及洛伐他汀腹腔注射。他汀类药物可用于治疗眼内炎症。(c)2006爱思唯尔有限公司保留所有权利。
Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are approved for cholesterol reduction and are commonly used to treat atherosclerosis and coronary artery disease. Statins may also be potent immunomodulatory agents and may be beneficial in the treatment of autoimmune diseases. In this study, we investigated therapeutic effects of atorvastatin and lovastatin on experimental autoimmune uveoretinitis (EAU). EAU was induced in Lewis rats using bovine S-antigen (S-Ag) peptide. Atorvastatin was suspended in 0.5% aqueous methylcellulose and was administered orally at a dose of 10 mg/kg and at a low-dose of 1 mg/kg. Lovastatin was dissolved in DMSO:PBS (1: 1) and was administered by intraperitoneal (i.p.) injection at a dose of 2 mg/kg. Both statin treatments were initiated after the clinical onset once daily for 14 days. The rats were examined every other day for clinical signs of EAU. The histological scores and delayed-type hypersensitivity (DTH) were evaluated on day 28 post-immunization. Morphologic and immunohistochemical examinations were performed with light and confocal microscopy, respectively. Lymphocyte proliferation was measured by [3 H]thymidine incorporation into antigen-stimulated T cells from inguinal lymph nodes. After 72 h, supernatants were collected and assayed for IFN-gamma by ELISA. Clinical and histological scores of EAU were decreased in both the atorvastatin (10 mg/kg)- and lovastatin (2 mg/kg)-treated groups. The invasion of T cells and macrophages, and Muller cell proliferation, were inhibited in both atorvastatin- and lovastatin-treated groups. DTH was significantly inhibited in both groups, compared with vehicle-treated groups (controls). Lymphocyte proliferation assay demonstrated decreased proliferation in the presence of 25 mu g/ml S-Ag peptide in both groups, compared with controls. In the supernatants of lymph node cells stimulated with S-Ag peptide (5 mu g/ml), 77 or 87% inhibition of IFN-gamma production was observed in rats treated with atorvastatin or lovastatin, respectively, compared with controls. The current results indicate that atorvastatin administrated orally following the clinical onset has therapeutic effect in EAU as well as lovastatin administrated intraperitoneally. Statins may be useful for treating intraocular inflammation. (c) 2006 Elsevier Ltd. All rights reserved.