Tu1641 Effects of Lubiprostone in a Porcine Model of Stress-Induced Intestinal Barrier Injury

Polyunsaturated fatty acid (PUFA) metabolism provides eicosanoid and docosanoid mediators that contribute to inflammation and to its resolution.In inflammatory bowel diseases, the homeostasis between these two types of metabolites is dysregulated.The aim of our study was to investigate the effect of two anti-inflammatory drugs (5-ASA and dexamethasone) on PUFA metabolites pattern in mice colitis.Methods: 5 groups of mice were treated with DSS 3% in drinking water to induce colitis and with 5-ASA (100 mg/kg), dexamethasone (DEX, 0.6 mg/kg) or their vehicle.After 7 days, colons were removed and inflammation evaluated by micro and macroscopic damages scores and myeloperoxidase activity (MPO).Eicosanoids and docosanoids from mouse colon were quantified by liquid chromatography tandem mass spectrometry.N-6 eicosanoids quantified were product of arachidonic acid metabolism by lipoxygenase (15-hydroxyeicosatetraenoic acid (15-HETE), 12-HETE, 8-HETE, 5-HETE, lipoxin A4 and B4, leukotriene B4 (LtB 4 ) and 5-oxoeicosatetraenoic acid (5-oxo-ETE)), by cyclooxygenase (6-keto-prostaglandin F1α (6-k-PGF 1 α), thromboxane B2 (TxB 2 ), 8-iso-PGA 2 and PGE 2 ), by cytochrome epoxygenase (5,6-, 8,9-, 11,12-and 14,15epoxyeicosatrienoic acid).N-3 eicosanoids and docosanoids quantified were metabolites of eicosapentaenoic acid (PGE 3 and LtB 5 ) and docosahexaenoic acid (resolvin D1, maresin-1, protectin (Pdx), 17-hydroxy-docosahexaenoic (17-HDoHE) and 14-HDoHE).Results: In vehicle treated mice, DSS augmented intestinal macro and microscopic damage score, MPO activity and weight lost compared to control animals.PUFA metabolite analysis in these samples revealed increased levels of pro-inflammatory (TxB 2 , PGE 2 , 5-, 8-HETE, 5-oxo-ETE and LtB 4 ) and pro-resolving mediators (17-HDoHE, 14-HDoHE and Pdx).5-ASA treatment decreased slightly damage score but has no effect on weight lost and MPO activity.This treatment only decreased the quantity of 5-HETE.Interestingly, concentration of two polymorphonuclear chemoattractant (5-oxo-ETE and LtB 4 ) correlated to MPO.DEX treatment decreased MPO activity and the concentration of pro-inflammatory and pro-resolving PUFA metabolites but increased the other inflammatory parameters.Moreover, in DSS/dexamethasone treated group, the concentration of PDx and 17-HDoHE correlated with microscopic damage score, and 5-oxo-ETE and LtB4 with MPO.Conclusions: In DSS colitis, 5-ASA did not decrease pro-inflammatory PUFA metabolites and only slightly diminished inflammation.In contrast, dexamethasone decreased both pro-inflammatory and pro-resolving metabolites, as well as MPO activity but failed to prevent all the others signs of colitis.These results suggest that the concentration of some PUFA metabolites correlates with specific parameters of inflammation and might explain the effects or lack of effects of drugs treatments.