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The resolution of inflammation is an active process orchestrated by specialized proresolving lipid mediators (SPM) that limit the host response within the affected tissue; failure of effective resolution may lead to tissue injury. Because persistence of inflammatory signals is a main feature of chronic inflammatory conditions, including inflammatory bowel diseases (IBDs), herein we investigate expression and functions of SPM in intestinal inflammation. Targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics was used to identify SPMs fromn-3 polyunsaturated fatty acids in human IBD colon biopsies, quantifying a significant upregulation of the resolvin and protectin pathway compared with normal gut tissue. Systemic treatment with protectin (PD)1n-3 DPA or resolvin (Rv)D5n-3 DPA protected against colitis and intestinal ischemia/reperfusion-induced inflammation in mice. Inhibition of 15-lipoxygenase activity reduced PD1n-3 DPA and augmented intestinal inflammation in experimental colitis. Intravital microscopy of mouse mesenteric venules demonstrated that PD1n-3 DPA and RvD5n-3 DPA decreased the extent of leukocyte adhesion and emigration following ischemia-reperfusion. These data were translated by assessing human neutrophil-endothelial interactions under flow: PD1n-3 DPA and RvD5n-3 DPA reduced cell adhesion onto TNF-α-activated human endothelial monolayers. In conclusion, we propose that innovative therapies based on n-3 DPA-derived mediators could be developed to enable antiinflammatory and tissue protective effects in inflammatory pathologies of the gut. [ABSTRACT FROM AUTHOR]