Charles N. Serhan
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women’s Hospital & Harvard Medical School, Boston, Massachusetts, 02115
Endogenous mechanisms controlling inflammation are of paramount importance because persistent and chronic inflammation can impact all organs and tissues throughout the body and are involved in many widely occurring diseases. Recent advances in our appreciation of the molecular mechanisms in resolution of acute inflammation (RoI) and ischemia-reperfusion injury systematically uncovered a novel genus of potent pro-resolving autacoid families, each biosynthesized from essential polyunsaturated fatty acids (PUFA) to activate potent responses not shared by the substrate. These include the resolvins (Rv), protectins (PD) and maresins (MaR), collectively termedspecialized proresolving mediators (SPM) that act in pico-nanogram range. SPM are temporally and spatially biosynthesized by resolving-inflammatory exudates, which proved to evoke potent antiinflammatory and pro-resolving actions as well as enhance microbial clearance. The potent SPM actions and complete structures are confirmed, which also permitted use of LC-MS-MS-based metabololipidomics to identify SPM in human and murine tissues (i.e. peripheral blood, breast milk, adipose, lymphoid, placenta), isolated human cells types (e.g. apoptotic human neutrophils, microparticles and macrophage phenotypes M1, M2), fish and diminished SPM in human pathologies e.g. breath condensates, Alzheimer brain, and synovial fluids from rheumatoid patients (CN Serhan Nature June vol 510, 2014 doi:10.1038/nature13479). Specific SPM demonstrate potent and stereoselective actions that involve specific G-protein-coupled receptors and are not immunosuppressive. Lipid mediator-metabololipidomics with selflimited resolving inflammatory exudates and human tissues demonstrated temporal orchestration of the SPM, i.e. RvD1 and RvD2 antecede RvD3, and MaR1 in mice and human tissues (Colas et al. AJP 2014). Many of the SPM born in inflammation-resolution are now shown to have potent actions and roles within host defense against bacteria and virus, pain, organ protection, tissue regeneration, exercise and neurobiology/cognitive function. This Plenary Lecture will update advances in SPM mechanisms in RoI, their new sites of formation and novel actions that opened the door for their role(s) in resolution physiology and pharmacology. Together, these new SPM families provide opportunities for resolution-based pharmacology and resolution physiology.