Abstract
Resolvins of the D-series are specialized pro-resolving lipid mediators that regulate cellular response by orchestrating resolution networks involved in host responses to injury and infection. Here, endogenous resolvin D4 was identified in human tissues and found to persist late into the resolution phase of acute murine Staphylococcus aureus infections. Completion of the first total synthesis of resolvin D4 established the absolute stereochemical configuration of RvD4 confirmed by matching with endogenous RvD4 from resolving exudates in dorsal pouch S. aureus infections. In vivo, RvD4 (ng/mouse) reduced neutrophilic infiltration (~40%) and enhanced uptake of apoptotic PMN (51%) by human dermal fibroblasts at concentrations as low as 0.1 nM. These results establish the complete stereochemistry of RvD4 as 4S,5R,17S-trihydroxydocosa-6E,8E,10Z,13Z,15E,19Z-hexaenoic acid and its novel pro-resolving actions in S. aureus infections as well as its potent ability to stimulate clearance of apoptotic cells by skin fibroblasts.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Anti-Inflammatory Agents, Non-Steroidal / chemistry
-
Anti-Inflammatory Agents, Non-Steroidal / metabolism
-
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
-
Apoptosis / drug effects
-
Docosahexaenoic Acids / biosynthesis
-
Docosahexaenoic Acids / chemistry
-
Docosahexaenoic Acids / pharmacology*
-
Fibroblasts / cytology
-
Fibroblasts / drug effects
-
Fibroblasts / immunology
-
Host-Pathogen Interactions
-
Humans
-
Male
-
Mice
-
Neutrophil Infiltration / drug effects
-
Neutrophils / drug effects
-
Neutrophils / immunology
-
Neutrophils / pathology
-
Peritonitis / drug therapy*
-
Peritonitis / immunology
-
Peritonitis / microbiology
-
Skin / drug effects
-
Skin / immunology
-
Skin / microbiology
-
Staphylococcal Skin Infections / drug therapy*
-
Staphylococcal Skin Infections / immunology
-
Staphylococcal Skin Infections / microbiology
-
Staphylococcus aureus / drug effects*
-
Staphylococcus aureus / growth & development
-
Staphylococcus aureus / pathogenicity
Substances
-
Anti-Inflammatory Agents, Non-Steroidal
-
Docosahexaenoic Acids