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?

溃疡性结肠炎（UC）是结肠的一种慢性炎症。目前的治疗旨在抑制炎症，但往往效果不佳。花生四烯酸（AA）级联是调节炎症的主要内源性途径；事实上，临床上公认的非甾体类抗炎药就是针对这个系统的。我们的研究表明，n-3多不饱和脂肪酸（n-3- pufa）对啮齿动物结肠炎模型具有很强的保护作用。内源性n3/6-PUFA比值与观察到的抗炎组织保护作用相关。虽然n-3-PUFA发挥这些生物效应的分子机制尚不完全清楚，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，并且它们也可能成为治疗人类炎症的新方法。在膳食中补充二十二碳六烯酸（DHA）和二十碳五烯酸（EPA）后，我们观察到它们的血浆细胞色素P450单加氧酶（CYP）衍生的脂质介质水平急剧增加。以类似的方式从花生四烯酸（AA）衍生的环氧脂肪酸具有很强的抗炎作用。考虑到最近的研究表明DHA和EPA环氧化物在疼痛和血管扩张方面比AA环氧化物具有更高的生物活性，本项目的中心假设是：DHA和EPA的环氧代谢物对实验性结肠炎的抗炎作用有显著贡献。我们将通过研究(1)增加的aa衍生环氧代谢物浓度和(2)增加的n-3环氧FA对大鼠和小鼠不同结肠炎模型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）会引起AA环氧代谢物的积累。n3-PUFA环氧化物代谢物的积累将通过(a)通过膳食补充或转基因方法（可以合成n-3 pufa的脂肪-1小鼠）增加组织中n-3- pufa的含量来实现，在另一个步骤(b)将与sEHi治疗相结合。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，该项目将为大鼠和小鼠结肠炎模型中花生四烯酸以及DHA和EPA酸衍生的环氧脂质介质的生物学提供基础信息。此外，提出的实验可能为将sEHi与DHA和EPA联合用于UC治疗的研究奠定基础：n-3 pufa -乙酯是处方药，并且有几种sEHi处于药物开发后期，这使得本文提出的实验研究的结果不太远地从实验台转移到临床是一种真正的可能性。

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.