瑞舒伐他汀 E1 可改善干眼模型小鼠的泪液生成并减轻炎症。
Resolvin E1 improves tear production and decreases inflammation in a dry eye mouse model.
机构信息
Neuroscience Center of Excellence and the Department of Ophthalmology, Louisiana State University Health Sciences Center , New Orleans, LA 70112, USA.
出版信息
J Ocul Pharmacol Ther. 2010 Oct;26(5):431-9. doi: 10.1089/jop.2010.0019.
PURPOSE
Dry eye (DE) is a common ocular surface disease, particularly among women and the elderly, with chronic symptoms of eye irritation and, in severe cases, blurred vision. Several studies have shown that there is an inflammatory component in DE, although the pathogenesis is not thoroughly understood. Resolvin E1 (RvE1; RX-10001) is an endogenous mediator derived from the omega-3 polyunsaturated fatty acid eicosapentaenoic acid and is involved in inflammation resolution and tissue protection. Here we investigated the role of RvE1 in a DE mouse model.
METHODS
Thirteen- to 14-week-old female BALB/C mice were exposed to desiccating conditions. One week after DE exposure, animals were treated topically with drug or vehicle 4 times per day for an additional week. Controls were nontreated animals placed in a normal environment. Schirmer's test was performed before treatment initiation and at days 2 and 4 after treatment. Density of corneal epithelial cells was analyzed in vivo using the Rostock Cornea Module of the Heidelberg Retina Tomograph (HRT-II). Corneas were processed using Western blot analysis and immunofluorescence examination.
RESULTS
Schirmer's test showed a significant decrease in tear production in DE compared with controls. There was no change at 2 and 4 days after treatment with the vehicle, but a significant increase was observed at 2 and 4 days in the RvE1-treated group. The density of the superficial epithelial cells showed a significant decrease after DE compared with controls, which increased after 7 days of RvE1 treatment. Western blot analysis showed that α-smooth muscle actin and cyclooxygenase-2 (COX-2) expression were strongly upregulated after DE and decreased after 7 days of RvE1 treatment. Immunofluorescence confirmed strong positive staining of α-smooth muscle actin and COX-2 in stroma and/or in epithelia after DE, which decreased with RvE1 treatment. The percentage of infiltrating CD⁴+ T cells and CD11b+ cells decreased after RvE1 treatment when compared with DE.
CONCLUSION
RvE1 promotes tear production, corneal epithelial integrity, and a decrease in inflammatory inducible COX-2. In the stroma, RvE1 inhibits keratocyte transformation to myofibroblasts and lowers the number of monocytes/macrophages in this DE mouse model. These results suggest that RvE1 and similar resolvin analogs have therapeutic potential in the treatment of DE.
目的
干眼症（DE）是一种常见的眼表疾病，尤其常见于女性和老年人，其慢性症状为眼部刺激，在严重情况下还会导致视力模糊。几项研究表明，DE 存在炎症成分，尽管其发病机制尚不清楚。解析素 E1（RvE1；RX-10001）是一种内源性介质，源自 ω-3 多不饱和脂肪酸二十碳五烯酸，参与炎症消退和组织保护。在此，我们研究了 RvE1 在 DE 小鼠模型中的作用。
方法
13 至 14 周龄雌性 BALB/C 小鼠暴露于干燥环境中。DE 暴露一周后，动物每天接受 4 次药物或载体局部治疗，再持续一周。对照组为置于正常环境中的未治疗动物。在治疗开始前以及治疗后第 2 天和第 4 天进行 Schirmer 测试。使用海德堡视网膜断层扫描仪（HRT-II）的 Rostock 角膜模块对活体角膜上皮细胞密度进行分析。通过 Western blot 分析和免疫荧光检查处理角膜。
结果
Schirmer 测试显示，与对照组相比，DE 组的泪液产生量显著减少。载体治疗后第 2 天和第 4 天没有变化，但 RvE1 治疗组的泪液产生量显著增加。与对照组相比，DE 后角膜上皮细胞的密度显著降低，而 RvE1 治疗 7 天后则增加。Western blot 分析显示，DE 后 α-平滑肌肌动蛋白和环氧化酶-2（COX-2）表达强烈上调，RvE1 治疗 7 天后表达下调。免疫荧光证实，DE 后基质和/或上皮中 α-平滑肌肌动蛋白和 COX-2 的阳性染色强烈，而 RvE1 治疗后则减少。与 DE 相比，RvE1 治疗后浸润的 CD⁴+T 细胞和 CD11b+细胞的百分比降低。
结论
RvE1 促进泪液产生、角膜上皮完整性，并降低诱导型 COX-2 的炎症。在基质中，RvE1 抑制角膜细胞向肌成纤维细胞的转化，并降低这种 DE 小鼠模型中单核细胞/巨噬细胞的数量。这些结果表明，RvE1 和类似的解析素类似物在治疗 DE 方面具有治疗潜力。
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