Uchida Takatoshi, Honjo Megumi, Yamagishi Reiko, Aihara Makoto
Department of Ophthalmology, Graduate School of Medicine, the University of Tokyo, Japan.
Invest Ophthalmol Vis Sci. 2017 Oct 1;58(12):5584-5593. doi: 10.1167/iovs.17-22679.
To investigate the anti-inflammatory properties of ripasudil, a Rho kinase (ROCK) inhibitor, using endotoxin-induced uveitis (EIU) in rats.
Endotoxin-induced uveitis was induced by footpad injection of lipopolysaccharide (LPS). Ripasudil was administered intraperitoneally 1 hour before and after LPS injection. The aqueous humor was collected 24 hours after injection, and the infiltrating cells, protein concentration, and levels of monocyte chemotactic protein-1 (MCP-1) were determined. Infiltrating cells in the iris ciliary body (ICB) and adherent leukocytes in retinal vessels were evaluated. The mRNA levels of IL-1β, IL-6, TNF-α, and MCP-1 in the retina and ICB were determined. A mouse macrophage cell line, RAW264.7, was stimulated with LPS in the presence or absence of ripasudil, and the expression of MCP-1 and nuclear translocation of nuclear factor (NF)-κB was analyzed.
Ripasudil significantly reduced infiltrating cells and protein exudation in the aqueous humor, as well as the number of infiltrating cells in the ICB and adherent leukocytes in retinal vessels in EIU. Additionally, the protein level of MCP-1 in the aqueous humor and mRNA levels of IL-1β, IL-6, TNF-α, MCP-1, and intercellular adhesion molecule-1 in the ICB and retina were suppressed by ripasudil. The production of MCP-1 and nuclear translocation of NF-κB in RAW264.7 cells were also suppressed by ripasudil.
The Rho/ROCK pathway plays a role in adhesion molecule expression and inflammatory cell infiltration in EIU, and ripasudil is a potent anti-inflammatory agent against ocular inflammatory diseases, including acute uveitis and possibly uveitic glaucoma.
利用大鼠内毒素诱导性葡萄膜炎（EIU）研究Rho激酶（ROCK）抑制剂ripasudil的抗炎特性。
通过足垫注射脂多糖（LPS）诱导内毒素诱导性葡萄膜炎。在LPS注射前1小时和注射后，腹腔注射ripasudil。注射后24小时收集房水，测定浸润细胞、蛋白质浓度和单核细胞趋化蛋白-1（MCP-1）水平。评估虹膜睫状体（ICB）中的浸润细胞和视网膜血管中的黏附白细胞。测定视网膜和ICB中白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和MCP-1的mRNA水平。在有或没有ripasudil存在的情况下，用LPS刺激小鼠巨噬细胞系RAW264.7，并分析MCP-1的表达和核因子（NF）-κB的核转位。
ripasudil显著减少了EIU中房水中的浸润细胞和蛋白质渗出，以及ICB中的浸润细胞数量和视网膜血管中的黏附白细胞数量。此外，ripasudil抑制了房水中MCP-1的蛋白质水平以及ICB和视网膜中IL-1β、IL-6、TNF-α、MCP-1和细胞间黏附分子-1的mRNA水平。ripasudil还抑制了RAW264.7细胞中MCP-1的产生和NF-κB的核转位。
Rho/ROCK通路在EIU中的黏附分子表达和炎性细胞浸润中起作用，ripasudil是一种有效的抗炎药物，可用于治疗眼部炎性疾病，包括急性葡萄膜炎以及可能的葡萄膜炎性青光眼。
