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Proc Natl Acad Sci U S A. 2017 Apr 11;114(15):3963-3968. doi: 10.1073/pnas.1617290114. Epub 2017 Mar 29.

Protectin D1n-3 DPA and resolvin D5n-3 DPA are effectors of intestinal protection.

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The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115.
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, N-0316 Oslo, Norway.
Department of Internal Medicine and Digestive Diseases, Pole Digestif, Centre Hospitalier Universitaire (CHU), 31059 Toulouse, France.
Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, 31300 Toulouse, France.
Unit 1220, INSERM, 31300 Toulouse, France.
Unit 1416, Institut National de la Recherche Agronomique (INRA), 31300 Toulouse, France.
École Nationale Vétérinaire de Toulouse (ENVT), 31300 Toulouse, France.
Université Paul Sabatier (UPS), 31300 Toulouse, France.
The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom;


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 from n-3 polyunsaturated fatty acids in human IBD colon biopsies, quantifying a significant up-regulation 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.


inflammation resolution; intravital microscopy; neutrophils; omega-3 fatty acids; specialized proresolving mediators

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