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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.

Author information

1
The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
2
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.
3
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, N-0316 Oslo, Norway.
4
Department of Internal Medicine and Digestive Diseases, Pole Digestif, Centre Hospitalier Universitaire (CHU), 31059 Toulouse, France.
5
Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, 31300 Toulouse, France.
6
Unit 1220, INSERM, 31300 Toulouse, France.
7
Unit 1416, Institut National de la Recherche Agronomique (INRA), 31300 Toulouse, France.
8
École Nationale Vétérinaire de Toulouse (ENVT), 31300 Toulouse, France.
9
Université Paul Sabatier (UPS), 31300 Toulouse, France.
10
The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; m.perretti@qmul.ac.uk.

Abstract

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.

KEYWORDS:

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

PMID:
28356517
PMCID:
PMC5393238
DOI:
10.1073/pnas.1617290114
[Indexed for MEDLINE]
Free PMC Article

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