Resolvin D4 Potent Antiiinflammatory Proresolving Actions Confirmed via Total Synthesis

Abstract

Resolvins are a family of structurally distinct pro-resolving lipid mediators biosynthesized from docosahexaenoic acid (DHA) during the resolution of acute inflammation. This family of compounds demonstrates distinct actions regulating neutrophil trafficking as well as the clearance of apoptotic PMN and cellular debris. Here we report for the first time the complete stereochemical assignment of a novel mediator termed Resolvin D4, (RvD4), as 4S,5R, 17S-trihydroxydocosa-6E,8E,10Z, 13Z, 15E-hexaenoic acid, produced by human macrophage and murine resolving exudates. For the absolute structural confirmation synthetic counterparts were achieved by the use of total organic synthesis from chiral pure precursors and matched with isolated endogenous material. Among our findings synthetic RvD4 exhibits potent actions in vivo by reducing infiltration of neutrophils and ultimately reducing murine peritonitis and dermal inflammation. Administration of Resolvin D4 promotes the clearance of apoptotic PMN by human macrophage and dermal fibroblasts at doses as low as 1 nM. Additionally Resolvin D4 was identified in human plasma, human breast milk as well as murine brain and sardines suggesting an evolutionary conservation in structure across several species. These selective actions at a picomolar concetration have implications to control a number diseases associated with inflammation.