Life of resolvins: Synthesis, bioactions and metabolic inactivation of novel anti-inflammatory and pro-resolving mediators

Acute inflammation is an essential event in host defense, but uncontrolled inflammatory status is closely associated with both classic inflammatory diseases and many other widely occurring diseases.;Lipid autacoids play key roles in the inflammatory process. Recently, a novel genus of lipid mediators derived from omega-3 polyunsaturated fatty acids has been uncovered. Named resolvins and protectins, these lipid mediators reduce inflammation and facilitate resolution, both in cellular systems and complex experimental diseases. To investigate molecular mechanisms, this dissertation investigated in vivo synthesis, bioactions and metabolic inactivation of eicosapentaenoic acid-derived resolvins.;A new active mediator was found from PMN incubation with E series resolvin precursor 18-hydroxyeicosapentaenoate. This molecule was assigned 5S,18-dihydroxy-eicosapentaenoate and coined resolvin E2 (RvE2), as a novel member of resolvin family.;RvE2 showed potent anti-inflammatory activities with distinct site of actions. Anti-inflammatory and pro-resolving actions with human peripheral blood leukocytes were investigated and specific interaction with human neutrophil were confirmed. RvE2 was identified in the initiation as well as the late resolution phase of murine peritonitis and is present in human plasma. These findings suggest a role of RvE2 as an early endogenous regulator of acute inflammation.;Since complete resolution of inflammation requires removal of inflammation-related mediators, the local metabolic inactivation of resolvin E1 (RvE1) was assessed. The metabolic profiles of diverse human and mouse tissue were elucidated and the RvE1 metabolome established. While most of further metabolites were found inactive, a stable analog of RvE1 was chemically prepared that resisted inactivation and retained bioactivity.;New E series resolvin biosynthesis pathways were also investigated. 18S-hydroxyeicosapentaenoate was identified in human plasma and macrophage incubation, using a chiral LC-MS-MS lipidomics. The identification of 18S-hydroxyeicosapentaenoate suggests parallel biosynthetic pathways. To support this, the new 18S-epimer of RvE1 was chemically prepared and its activity was compared to RvE1.;Taken together, a comprehensive approach regarding the biosynthesis, actions and metabolic inactivation of E series resolvins were carried out using multi-pronged biochemical and chemical approaches. In addition to elucidating endogenous mechanisms of biosynthesis, actions and inactivation, these results also provide knowledge for novel therapeutic targets to modulate inflammation and its resolution.