The combination of long chain n-3 polyunsaturated fatty acids and blockade of soluble epoxide hydrolase: A new anti-inflammatory therapy for the treatment of Ulcerative colitis?

长链n-3多不饱和脂肪酸与可溶性环氧化物水解酶阻断的组合：治疗溃疡性结肠炎的新抗炎疗法？

• 批准号: 274914120
• 负责人: Professor Dr. Nils Helge Schebb
• 金额: --
• 依托单位: Arbeitsgruppe Lebensmittelchemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/274914120?language=en
• 关键词: combination; long; chain; polyunsaturated; fatty

Ulcerative Colitis (UC) is a chronic inflammatory condition of the colon. Current treatments aim at the suppression of the inflammation but are often not effective. The arachidonic acid (AA) cascade is a central endogenous pathway for the regulation of inflammation; indeed, the clinically well-established non-steroidal anti-inflammatory drugs target this system. Our studies indicate that n-3 polyunsaturated fatty acids (n-3-PUFA) have strong protective effects in rodent models of colitis. The endogenous n3/6-PUFA ratio correlates with the observed anti-inflammatory tissue protective effects. While the molecular mechanisms by which n-3-PUFA exert these biological effects are not completely understood, there is accumulating evidence that n-3-PUFA derived lipid mediators might play an anti-inflammatory role in this context and that they could be new treatment approaches also in human inflammatory conditions. Following dietary supplementation of human subjects with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) we observed a dramatic increase in the plasma levels of their cytochrome P450 monooxygenase (CYP) derived lipid mediators. Epoxy-fatty acids derived in an analogous manner from arachidonic acid (AA) possess strong anti-inflammatory action. Taking into account that recent studies indicate that DHA and EPA epoxides have even higher biological activity with regards to pain and vasodilatation than AA epoxides the central hypothesis of this project is: Epoxy metabolites from DHA and EPA contribute significantly to their anti-inflammatory effects in experimental colitis. We will address this hypothesis by investigating the effects of (1) increased AA-derived epoxy metabolite concentrations and (2) increased n-3 epoxy FA on colitis in different colitis models in rats and mice. Accumulation of AA epoxy metabolites will be caused by administration of soluble epoxide hydrolase inhibitors (sEHi). Accumulation of n3-PUFA epoxide metabolites will be achieved by (a) increasing the tissue n-3-PUFA content using dietary supplementation or the transgenic approach (fat-1 mice which can synthesize n-3 PUFAs) and in another step (b) this will be combined with sEHi treatment. Changes in patterns of lipid mediators and fatty acids will be monitored by targeted metabolomics techniques and correlated with biological endpoints of inflammation using methods of histology, immunology and molecular biology. This project will thus provide fundamental information about the biology of epoxy lipid mediators derived from arachidonic acid, as well as from DHA and EPA acids, in colitis models in rats and mice. Moreover, the proposed experiments might form a basis for the study of sEHi in combination with DHA and EPA as treatment for UC: n-3 PUFA-ethyl esters are prescription drugs and several sEHi are in late drug development making a not too distant transfer from bench-to-bedside of the results from the experimental study proposed here a real possibility.

溃疡性结肠炎（UC）是结肠的慢性炎症性病症。目前的治疗旨在抑制炎症，但通常无效。花生四烯酸（AA）级联是调节炎症的中心内源性途径;事实上，临床上成熟的非甾体抗炎药靶向该系统。我们的研究表明，n-3多不饱和脂肪酸（n-3-PUFA）在啮齿动物结肠炎模型中具有很强的保护作用。内源性n3/6-PUFA比率与观察到的抗炎组织保护作用相关。虽然n-3-PUFA发挥这些生物学作用的分子机制尚未完全了解，但越来越多的证据表明，n-3-PUFA衍生的脂质介质可能在这种情况下发挥抗炎作用，并且它们也可能是人类炎症状况的新治疗方法。在饮食补充二十二碳六烯酸（DHA）和二十碳五烯酸（EPA）的人类受试者，我们观察到他们的细胞色素P450单加氧酶（CYP）衍生的脂质介质的血浆水平显着增加。以类似方式从花生四烯酸（AA）衍生的环氧脂肪酸具有强抗炎作用。考虑到最近的研究表明，DHA和EPA环氧化物在疼痛和血管舒张方面比AA环氧化物具有更高的生物活性，该项目的中心假设是：DHA和EPA的环氧代谢物对实验性结肠炎的抗炎作用有显着贡献。我们将通过研究（1）AA衍生环氧代谢物浓度增加和（2）n-3环氧FA增加对大鼠和小鼠不同结肠炎模型中结肠炎的影响来解决这一假设。可溶性环氧化物水解酶抑制剂（sEHi）给药将导致AA环氧代谢物蓄积。n3-PUFA环氧化物代谢物的积累将通过以下方式实现：（a）使用膳食补充剂或转基因方法（可以合成n-3 PUFA的fat-1小鼠）增加组织n-3-PUFA含量，并且在另一步骤（B）中，这将与sEHi处理组合。脂质介质和脂肪酸模式的变化将通过靶向代谢组学技术进行监测，并使用组织学、免疫学和分子生物学方法与炎症的生物学终点相关联。因此，该项目将提供有关在大鼠和小鼠结肠炎模型中源自花生四烯酸以及DHA和EPA酸的环氧脂质介质的生物学的基本信息。此外，所提出的实验可能形成研究sEHi与DHA和EPA组合作为UC治疗的基础：n-3 PUFA-乙酯是处方药，并且几种sEHi处于后期药物开发中，使得来自本文提出的实验研究的结果从实验室到床边的不太远的转移成为真实的可能性。