Rheumatoid arthritis is a common systemic inflammatory autoimmune disease characterized by damage to joints, inflammation and pain. It is driven by an increase of inflammatory cytokines and lipids mediators such as prostaglandins. Epoxides of polyunsaturated fatty acids (PUFAs) are lipid chemical mediators in a group of regulatory compounds termed eicosanoids. These epoxy fatty acids (EpFA) have resolutive functions but are rapidly metabolized by the soluble epoxide hydrolase enzyme (sEH) into the corresponding diols. The pharmacological inhibition of sEH stabilizes EpFA from hydrolysis, improving their half-lives and biological effects. These anti-inflammatory EpFA, are analgesic in neuropathic and inflammatory pain conditions. Nonetheless, inhibition of sEH on arthritis and the resulting effects on eicosanoids profiles are little explored despite the physiological importance. In this study, we investigated the effect of sEH inhibition on collagen-induced arthritis (CIA) and its impact on the plasma eicosanoid profile. We measured the eicosanoid metabolites by LC–MS/MS-based lipidomic analysis. The treatment with a sEH inhibitor significantly modulated 11 out of 69 eicosanoids, including increased epoxides 12(13)-EpODE, 12(13)-EpOME, 13-oxo-ODE, 15-HEPE, 20-COOH-LTB4 and decreases several diols 15,6-DiHODE, 12,13-DiHOME, 14,15-DiHETrE, 5,6-DiHETrE and 16,17-DiHDPE. Overall the inhibition of sEH in the rheumatoid arthritis model enhanced epoxides generally considered anti-inflammatory or resolutive mediators and decreased several diols with inflammatory features. These findings support the hypothesis that inhibiting the sEH increases systemic EpFA levels, advancing the understanding of the impact of these lipid mediators as therapeutical targets.

类风湿性关节炎是一种常见的全身性炎症性自身免疫性疾病，以关节损伤、炎症和疼痛为特征。它是由炎症细胞因子和脂质介质（例如前列腺素）的增加驱动的。多不饱和脂肪酸 (PUFA) 的环氧化物是一组称为类二十烷酸的调节化合物中的脂质化学介质。这些环氧脂肪酸（EpFA）具有解析功能，但会被可溶性环氧化物水解酶（sEH）快速代谢成相应的二醇。sEH 的药理学抑制作用可稳定 EpFA 的水解，从而改善其半衰期和生物效应。这些抗炎 EpFA 对神经性疼痛和炎性疼痛有镇痛作用。尽管如此，尽管 sEH 具有生理重要性，但对关节炎的抑制作用以及由此产生的对类二十烷酸的影响却很少被探索。在这项研究中，我们研究了 sEH 抑制对胶原诱导性关节炎 (CIA) 的影响及其对血浆类二十烷酸谱的影响。我们通过基于 LC-MS/MS 的脂质组学分析测量了类二十烷酸代谢物。使用 sEH 抑制剂治疗可显着调节 69 种类二十烷酸中的 11 种，包括增加环氧化物 12(13)-EpODE、12(13)-EpOME、13-oxo-ODE、15-HEPE、20-COOH-LTB4 并减少多种二醇15,6-DiHODE、12,13-DiHOME、14,15-DiHETrE、5,6-DiHETrE 和 16,17-DiHDPE。总体而言，类风湿性关节炎模型中 sEH 的抑制增强了通常被认为是抗炎或溶解介质的环氧化物，并减少了几种具有炎症特征的二醇。这些发现支持了这样的假设：抑制 sEH 会增加全身 EpFA 水平，从而加深对这些脂质介质作为治疗靶点的影响的理解。