Suppression of ocular inflammation in endotoxin-induced uveitis by blocking the angiotensin II type 1 receptor
Suppression of ocular inflammation in endotoxin-induced uveitis by blocking the angiotensin II type 1 receptor
复制标题
DOI：
10.1167/iovs.04-1476
复制
发表时间：
2005-08-01
影响因子：
4.4
通讯作者：
Ishida, S
中科院分区：
文献类型：
--
作者：
Nagai, N;Oike, Y;Ishida, S
目的。目的探讨血管紧张素II 1型受体(AT1-R)信号转导通路在内毒素性葡萄膜炎(EIU)眼部炎症中的作用。免疫组织化学、RT-PCR和Western印迹分析AT1-R在小鼠视网膜中的组织定位、mRNA表达和蛋白水平。替米沙坦是一种被广泛用作降压药的AT1-R拮抗剂，每天10 mg/kg，连续5天，直到注射内毒素。给药24小时后，用刀豆蛋白A凝集素灌流标记技术检测白细胞与视网膜血管的粘附性。逆转录-聚合酶链式反应检测视网膜细胞间黏附分子-1(ICAM-1)的表达水平；结果视网膜血管AT1-R呈阳性反应。与正常对照组相比，患有EIU的小鼠视网膜AT1-RmRNA和蛋白水平显著升高。EIU动物还表现出渗入前房并黏附于视网膜血管的炎症细胞数量以及视网膜ICAM-1水平显著增加。与赋形剂治疗相比，替米沙坦可显著抑制EIU小鼠视网膜ICAM-1的表达和白细胞的黏附和渗透。替米沙坦治疗的EIU小鼠房水中蛋白质浓度低于赋形剂治疗的EIU小鼠，但差异无统计学意义。结论AT1-R信号通路阻断抑制了EIU模型中视网膜ICAM-1的表达，抑制了白细胞的黏附和渗透。这些结果表明，AT1-R拮抗剂有可能被用作减少眼部炎症的治疗剂。
PURPOSE. To examine whether the angiotensin II type 1 receptor (AT1-R) signaling plays a role in ocular inflammation in endotoxin-induced uveitis (EIU).METHODS. EIU was induced in C57BL/6 mice by a single intraperitoneal injection of 150 mu g lipopolysaccharide (LPS). Tissue localization, mRNA expression, and protein levels of AT1-R in murine retinas were examined by immunohistochemistry, RTPCR, and Western blot analyses, respectively. Telmisartan, an AT1-R antagonist widely used as an antihypertensive agent, was administered intraperitoneally at a dose of 10 mg/kg daily for 5 days until the injection of LPS. Twenty-four hours after administration, leukocyte adhesion to the retinal vasculature was evaluated with a concanavalin A lectin perfusion-labeling technique. Retinal mRNA and protein levels of intercellular adhesion molecule (ICAM)-1 were examined by RT-PCR and ELISA, respectively. Protein concentration and inflammatory cells in the aqueous humor were also measured.RESULTS. Retinal vessels were positive for AT1-R. In mice with EIU, retinal AT1-R mRNA and protein levels were significantly increased when compared to the normal control. EIU animals also showed significant increases in the number of inflammatory cells infiltrating the anterior chamber and adhering to the retinal vessels and in retinal ICAM-1 levels. Administration of telmisartan to EIU mice resulted in significant suppression of retinal ICAM-1 expression and leukocyte adhesion and infiltration compared with vehicle treatment. Protein concentration in the aqueous humor of telmisartan-treated EIU mice tended to be lower than that of vehicle-treated EIU mice, but the difference was not statistically significant.CONCLUSIONS. AT1-R signaling blockade inhibited retinal ICAM-1 upregulation and leukocyte adhesion and infiltration in the EIU model. These results suggest the potential use of an AT1-R antagonist as a therapeutic agent to reduce ocular inflammation.