title: Omega-3 fatty acid-derived mediators 17(R)-hydroxy docosahexaenoic acid, aspirin-triggered resolvin D1 and resolvin D2 prevent experimental colitis in mice.
abstract: Resolvins of the D series are generated from docosahexaenoic acid, which are enriched in fish oils and are believed to exert beneficial roles on diverse inflammatory disorders, including inflammatory bowel disease (IBD). In this study, we investigated the anti-inflammatory effects of the aspirin-triggered resolvin D1 (AT-RvD1), its precursor (17(R)-hydroxy docosahexaenoic acid [17R-HDHA]) and resolvin D2 (RvD2) in dextran sulfate sodium (DSS)- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Our results showed that the systemic treatment with AT-RvD1, RvD2, or 17R-HDHA in a nanogram range greatly improved disease activity index, body weight loss, colonic damage, and polymorphonuclear infiltration in both colitis experimental models. Moreover, these treatments reduced colonic cytokine levels for TNF-α, IL-1β, MIP-2, and CXCL1/KC, as well as mRNA expression of NF-κB and the adhesion molecules VCAM-1, ICAM-1, and LFA-1. Furthermore, AT-RvD1, but not RvD2 or 17R-HDHA, depended on lipoxin A4 receptor (ALX) activation to inhibit IL-6, MCP-1, IFN-γ, and TNF-α levels in bone marrow-derived macrophages stimulated with LPS. Similarly, ALX blockade reversed the beneficial effects of AT-RvD1 in DSS-induced colitis. To our knowledge, our findings showed for the first time the anti-inflammatory effects of resolvins of the D series and precursor 17R-HDHA in preventing experimental colitis. We also demonstrated the relevant role exerted by ALX activation on proresolving action of AT-RvD1. Moreover, AT-RvD1 showed a higher potency than 17R-HDHA and RvD2 in preventing DSS-induced colitis. The results suggest that these lipid mediators possess a greater efficacy when compared with other currently used IBD therapies, such as monoclonal anti-TNF, and have the potential to be used for treating IBD.
authors: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88049-900, Florianópolis, Santa Catarina 88049-900, Brazil.
authors: Allisson Freire
authors: AF
authors: Bento
authors: Rafaela Franco
authors: RF
authors: Claudino
authors: Rafael Cypriano
authors: RC
authors: Dutra
authors: Rodrigo
authors: R
authors: Marcon
authors: João B
authors: JB
authors: Calixto
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D016264:Dextran Sulfate / Q000633:toxicity; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000096:biosynthesis / Q000276:immunology; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D014301:Trinitrobenzenes / Q000009:adverse effects / Q000494:pharmacology; D014874:Water Pollutants, Chemical / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D016207:Cytokines; C469988:Fpr1 protein, mouse; D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; D014301:Trinitrobenzenes; D014874:Water Pollutants, Chemical; C518399:resolvin D1; C545423:resolvin D2; D004281:Docosahexaenoic Acids; C029222:sym-trinitrobenzene; D016264:Dextran Sulfate; C062894:17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid; D001241:Aspirin