McLellan Gillian J, Aktas Zeynep, Hennes-Beean Elizabeth, Kolb Aaron W, Larsen Inna V, Schmitz Emily J, Clausius Hilary R, Yang Jun, Hwang Sung Hee, Morisseau Christophe, Inceoglu Bora, Hammock Bruce D, Brandt Curtis R
Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, USA; Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, USA; Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Wisconsin, USA; Comparative Ophthalmic Research Laboratories, School of Veterinary Medicine, University of Wisconsin-Madison, Wisconsin, USA; Department of Ophthalmology and Visual Sciences, McPherson Eye Research Institute, University of Wisconsin-Madison, Wisconsin, USA.
Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, USA; Department of Surgical Sciences, Gazi University, Turkey.
J Ocul Biol. 2016 Jan;4(1). doi: 10.13188/2334-2838.1000024. Epub 2016 Jan 12.
Cytochrome P450 epoxygenase isozymes convert free arachidonic acid into eicosanoids named epoxyeicosatrienoic acids (EETs) that have roles in regulating inflammation. EETs are rapidly converted to dihydroxyeicosatrienoic acids (DiHETs) by soluble epoxide hydrolase (sEH). Little is known about the potential role of these metabolites in uveitis, but conversion of EETs to DiHETs could contribute to the inflammation. We tested a potent and orally available inhibitor of sEH for its ability to reduce ocular inflammation in a rabbit LPS-induced model of uveitis. Rabbits were treated by subcutaneous injection with the sEH inhibitor (UC1728, 3 mg/kg), or the vehicle control (PEG400) and uveitis was assessed at 6, 24 and 48 h post-intracameral LPS injection using a modified Hackett-McDonald scoring system. Eyes treated by intra-cameral injection of PBS, or by aseptic preparation served as further controls. Signs of inflammation in this model were mild and transient. Treatment with UC1728 did not significantly reduce inflammation compared to animals treated with the PEG400 vehicle. Blood levels of UC1728 were a thousand fold higher than the in vitro determined inhibitory potency (IC50) of the compound suggesting a significant degree of inhibition of sEH in the rabbit. The lack of efficacy suggests that sEH or its substrates the EETs may not be involved in mediating inflammation in this model of uveitis.
细胞色素P450环氧化酶同工酶将游离花生四烯酸转化为名为环氧二十碳三烯酸（EETs）的类花生酸，这些类花生酸在调节炎症中发挥作用。EETs可被可溶性环氧化物水解酶（sEH）迅速转化为二羟基二十碳三烯酸（DiHETs）。关于这些代谢产物在葡萄膜炎中的潜在作用知之甚少，但EETs向DiHETs的转化可能会加重炎症。我们测试了一种强效且口服可用的sEH抑制剂在兔脂多糖诱导的葡萄膜炎模型中减轻眼部炎症的能力。通过皮下注射sEH抑制剂（UC1728，3mg/kg）或溶剂对照（聚乙二醇400）对兔子进行治疗，并在房内注射脂多糖后6、24和48小时使用改良的哈克特-麦克唐纳评分系统评估葡萄膜炎。通过房内注射PBS或无菌制备处理的眼睛作为进一步对照。该模型中的炎症迹象轻微且短暂。与用聚乙二醇400溶剂处理的动物相比，用UC1728治疗并没有显著减轻炎症。UC1728的血药浓度比该化合物的体外测定抑制效力（IC50）高一千倍，这表明该化合物在兔子体内对sEH有显著程度的抑制作用。缺乏疗效表明sEH或其底物EETs可能不参与介导该葡萄膜炎模型中的炎症。
