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?

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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.