resolvin-d3 and Peritonitis

Resolution of infection and inflammation is governed by innate immune cells. The resolvin family of n-3 mediators produced by resolving exudates stimulates clearance of neutrophils and attenuates pro-inflammatory signals. Using metabololipidomics, endogenous resolvin D3 (RvD3) was identified in self-resolving exudates during active E. coli infection. Through a new, independent synthetic route for RvD3, we matched endogenous and synthetic RvD3 and determined that RvD3 (ng doses) potently reduced the resolution interval (R

Topics: Animals; Cytokines; Escherichia coli; Escherichia coli Infections; Fatty Acids, Unsaturated; Inflammation; Macrophages; Male; Mice; Neutrophils; Peritonitis

Aging is associated with an overt inflammatory phenotype and physiological decline. Specialized proresolving lipid mediators (SPMs) are endogenous autacoids that actively promote resolution of inflammation. In this study, we investigated resolution of acute inflammation in aging and the roles of SPMs. Using a self-resolving peritonitis and resolution indices coupled with lipid mediator metabololipidomics, we found that aged mice had both delayed resolution and reduced SPMs. The SPM precursor docosahexaenoic acid accelerated resolution via increased SPMs and promoted human monocyte reprogramming. In aged mice, novel nano-proresolving medicines carrying aspirin-triggered resolvins D1 and D3 reduced inflammation by promoting efferocytosis. These findings provide evidence for age-dependent resolution pathways in acute inflammation and novel means to activate resolution.

Topics: Aging; Animals; Aspirin; Autacoids; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Humans; Inflammation; Inflammation Mediators; Leukocytes, Mononuclear; Macrophages; Male; Metabolomics; Mice; Mice, Inbred BALB C; Nanomedicine; Peritonitis; Principal Component Analysis; Zymosan

Resolvins are a family of n-3 lipid mediators initially identified in resolving inflammatory exudates that temper inflammatory responses to promote catabasis. Here, temporal metabololipidomics with self-limited resolving exudates revealed that resolvin (Rv) D3 has a distinct time frame from other lipid mediators, appearing late in the resolution phase. Using synthetic materials prepared by stereocontrolled total organic synthesis and metabololipidomics, we established complete stereochemistry of RvD3 and its aspirin-triggered 17R-epimer (AT-RvD3). Both synthetic resolvins potently regulated neutrophils and mediators, reducing murine peritonitis and dermal inflammation. RvD3 and AT-RvD3 displayed leukocyte-directed actions, e.g., blocking human neutrophil transmigration and enhancing macrophage phagocytosis and efferocytosis. These results position RvD3 uniquely within the inflammation-resolution time frame to vantage and contribute to the beneficial actions of aspirin and essential n-3 fatty acids.

Topics: Animals; Aspirin; Cytokines; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Humans; Immunosuppressive Agents; Inflammation; Macrophages; Metabolome; Mice; Neutrophils; Peritonitis; Phagocytosis; Receptors, G-Protein-Coupled; Stereoisomerism; Tandem Mass Spectrometry