Elucidation of Resolvin and Protectin Sulfido‐Conjugated Mediators: New Pro‐Resolving and Tissue Regenerative Pathways

Abstract

Resolution of inflammation is an active cellular and biochemical process mediated by autacoids. Here, we investigated self‐limited infectious exudates for novel bioactive chemical signals in tissue regeneration and resolution. Using spleens from E. coli infected mice, self‐resolving infectious exudates, human spleens and blood from sepsis patients we identified two new families of potent molecules. Characterization of their physical properties and isotope tracking demonstrated that the bioactive structures contained a docosahexaenoate backbone and sulfido‐conjugated triene or tetraene double bond systems. Activated human phagocytes converted 17‐hydro(peroxy)‐4Z,7Z,10Z,13Z,15E,19Z‐docosahexaenoic acid to these bioactive molecules. Regeneration of injured planaria was accelerated with nanomolar amounts of 16‐glutathionyl, 17‐hydroxy‐docosahexaenoic acid and 16‐cysteinylglycinyl, 17‐hydroxy‐docosahexaenoic acid (coined protectin conjugates in tissue regeneration) as well as 8‐glutathionyl, 7,17‐dihydroxy‐docosahexaenoic acid and 8‐cysteinylglycinyl, 7,17‐dihydroxy‐docosahexaenoic acid (coined resolvin conjugates in tissue regeneration). Each protectin and resolvin sulfido‐conjugate stimulated human macrophage bacterial phagocytosis, phagolysosomal acidification and efferocytosis. Together these results identify two novel pathways and structural elucidation of new resolution moduli. These pathways and mediators display host protective, pro‐resolving and tissue regenerative actions, properties essential for tissue homeostasis.