Resolution Medicine: Steps to Uncovering the Specialized Pro-resolving Mediator Superfamily and Their Potent Functions in Resolving Inflammation.

Surgery, barrier breaks, injury, and microbial invasions initiate the cardinal signs of inflammation: heat, redness, swelling, and pain mediated by the classic prostaglandins. Tissue histology defined the acute inflammatory response, its initiation with leukocyte infiltration, and normally self-limited resolution phase. Resolution, once thought to be passive, is an active program accompanied by temporal biosynthesis of novel lipid mediators that activate clearance of apoptotic neutrophils (polymorphonuclear neutrophil-PMN) and cellular debris and limit the further PMN infiltration. Structural elucidation of these novel potent products demonstrated their biosynthesis from essential polyunsaturated fatty acids. The pro-resolving mediator superfamily includes lipoxins, resolvins, protectins, and maresins, which are each structurally distinct, their complete stereochemistry, biosynthesis, roles of epoxide intermediates, and potent functions all confirmed with total organic synthesis. Given their specialized new physiologic functions, they are grouped together based on this new function and termed the "specialized pro-resolving mediator" (SPM) superfamily. This chapter outlines, for the first time, the lines of reasoning and experimentation that led to SPM discovery and their physiologic functions along with evidence that establishes resolvin structures and biosynthesis which are conserved in evolution. Supplementation with omega-3 in humans increases SPMs. Leukocytes, muscle, and vagus nerve also produce SPMs. SPMs act on stem cells, are organ protective, and stimulate resolution by limiting the magnitude and duration of inflammation. SPMs reduce cancer burden, pain, neuroinflammation, and vascular inflammation. SPM mimetics demonstrate in pivotal human trials that activating endogenous resolution programs can control excessive and chronic inflammation. These results give a new platform for treating inflammation-associated diseases via resolution medicine.