Publications

• Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections.

  Dalli J., Chiang N., Serhan C.N.

  Endogenous mechanisms leading to host protection and resolution of infections without immunosuppression are of wide interest. Here we elucidate the structures of four new host-protective molecules produced in neutrophil-endothelial cocultures and present in human and mouse tissues after sterile in ... >> More

  Endogenous mechanisms leading to host protection and resolution of infections without immunosuppression are of wide interest. Here we elucidate the structures of four new host-protective molecules produced in neutrophil-endothelial cocultures and present in human and mouse tissues after sterile inflammation or infection. The bioactive molecules contain conjugated triene and diene double bonds, carry an alcohol at C13 and are derived from n-3 docosapentaenoic acid (DPA, C22:5). These compounds, termed 13-series resolvins (RvTs), demonstrated potent protective actions increasing mice survival during Escherichia coli infections. RvTs also regulated human and mouse phagocyte responses stimulating bacterial phagocytosis and regulating inflammasome components. Their biosynthesis during neutrophil-endothelial cell interactions was initiated by endothelial cyclooxygenase-2 (COX-2), increased by atorvastatin via S-nitrosylation of COX-2 and reduced by COX-2 inhibitors. The actions of atorvastatin and RvTs were additive in E. coli infections in mice, where they accelerated resolution of inflammation and increased survival >60%. Taken together, these results document host-protective molecules in bacterial infections, namely RvTs, derived from n-3 DPA via transcellular biosynthesis and increased by atorvastatin. These molecules regulate key innate protective responses in the resolution of infectious inflammation. << Less

  Nat. Med. 21:1071-1075(2015) [PubMed] [EuropePMC]

• Synthesis of 13(R)-Hydroxy-7Z,10Z,13R,14E,16Z,19Z Docosapentaenoic Acid (13R-HDPA) and Its Biosynthetic Conversion to the 13-Series Resolvins.

  Primdahl K.G., Aursnes M., Walker M.E., Colas R.A., Serhan C.N., Dalli J., Hansen T.V., Vik A.

  Specialized pro-resolving lipid mediators are biosynthesized during the resolution phase of acute inflammation from n-3 polyunsaturated fatty acids. Recently, the isolation and identification of the four novel mediators denoted 13-series resolvins, namely, RvT1 (1), RvT2 (2), RvT3 (3) and RvT4 (4) ... >> More

  Specialized pro-resolving lipid mediators are biosynthesized during the resolution phase of acute inflammation from n-3 polyunsaturated fatty acids. Recently, the isolation and identification of the four novel mediators denoted 13-series resolvins, namely, RvT1 (1), RvT2 (2), RvT3 (3) and RvT4 (4), were reported, which showed potent bioactions characteristic for specialized pro-resolving lipid mediators. Herein, based on results from LC/MS-MS metabololipidomics and the stereoselective synthesis of 13(R)-hydroxy-7Z,10Z,13R,14E,16Z,19Z docosapentaenoic acid (13R-HDPA, 5), we provide direct evidence that the four novel mediators 1-4 are all biosynthesized from the pivotal intermediate 5. The UV and LC/MS-MS results from synthetic 13R-HDPA (5) matched those from endogenously and biosynthetically produced material obtained from in vivo infectious exudates, endothelial cells, and human recombinant COX-2 enzyme. Stereochemically pure 5 was obtained with the use of a chiral pool starting material that installed the configuration at the C-13 atom as R. Two stereoselective Z-Wittig reactions and two Z-selective reductions of internal alkynes afforded the geometrically pure alkene moieties in 5. Incubation of 5 with isolated human neutrophils gave all four RvTs. The results presented herein provide new knowledge on the biosynthetic pathways and the enzymatic origin of RvTs 1-4. << Less

  J Nat Prod 79:2693-2702(2016) [PubMed] [EuropePMC]