Proresolving actions of a new resolvin D1 analog mimetic qualifies as an immunoresolvent

• Published in: American journal of physiology. Lung cellular and molecular physiology 2015-05, Vol.308 (9), p.L904-L911
• Main Authors: Orr, Sarah K, Colas, Romain A, Dalli, Jesmond, Chiang, Nan, Serhan, Charles N
• Format: Article
• Language: English
• Subjects: Animals; Call for Papers; Cells, Cultured; Docosahexaenoic Acids - chemistry; Docosahexaenoic Acids - metabolism; Docosahexaenoic Acids - pharmacology; E coli; Escherichia coli - drug effects; Escherichia coli Infections - drug therapy; Esters - chemical synthesis; Esters - chemistry; Humans; Inflammation - drug therapy; Leukocytes; Lipids; Lung - immunology; Lung - pathology; Lung diseases; Macrophages - drug effects; Macrophages - immunology; Metabolism; Mice; Neutrophil Infiltration - drug effects; Peritonitis - drug therapy; Phagocytes - immunology; Phagocytosis - drug effects; Phagocytosis - immunology; Receptors, G-Protein-Coupled - agonists; Reperfusion Injury - drug therapy; Reperfusion Injury - immunology; Rodents; Zymosan - immunology
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00370.2014

Resolution of inflammation is an active process driven by several new families of endogenous lipid mediators collectively coined specialized proresolving mediators (SPM). Here, we report a synthetic analog of resolvin D1 (RvD1) and aspirin-triggered RvD1, benzo-diacetylenic-17R-RvD1-methyl ester (BDA-RvD1), which was prepared using fewer steps than required for total organic synthesis of natural SPM. BDA-RvD1 was resistant to further metabolism by human recombinant 15-prostaglandin dehydrogenase, a major inactivation pathway for RvD1. In ischemia-reperfusion-initiated second organ injury, BDA-RvD1 intravenously (1 μg) reduced neutrophil infiltration into the lungs by 58 ± 9% and was significantly more potent than native RvD1. BDA-RvD1 at 100 ng/mouse also shortened the resolution interval, Ri, of Escherichia coli peritonitis with a similar potency as RvD1, by ~57%, from Ri 10.5 h to 4.5 h. With isolated human phagocytes, BDA-RvD1 at picomolar concentrations (10(-12) M) stimulated phagocytosis of zymosan A particles. BDA-RvD1 activated human recombinant G protein-coupled receptor 32/DRV1, an RvD1 receptor, in a dose-dependent manner. These results indicate that, both in vivo in mice and with isolated human cells, BDA-RvD1 shares defining proresolving actions of RvD1, including inhibiting leukocyte infiltration and stimulating phagocytosis. Moreover, they provide evidence for a new analog mimetic and example of an immunoresolvent, namely an agent that stimulates active resolution of inflammation, for a potential new therapeutic class.