A host’s normal protective response to tissue injury or pathogenic infection is acute inflammation. The condition of acute inflammation is created by the release of pro-inflammatory lipid mediators such as leukotrienes (LTs) and prostaglandins (PGs) that launch a series of signaling cascades to destroy invading pathogens and to repair damaged tissue (Libby 2007). The potent chemotactic agent leukotriene B4 (LTB4) promotes the recruitment of neutrophils (PMNs) to inflamed tissues, while the prostaglandins E2 and D2 (PGE2 and PGD2) further accelerate the inflammatory process. If left unchecked, the inflammatory response can initiate chronic systemic inflammatory disorders associated with cardiovascular disease, rheumatoid arthritis, periodontal disease, asthma, diabetes, inflammatory bowel disease (IBD), Alzheimer’s disease and age-related macular degeneration (AMD). The specific role by which inflammation contributes to their pathogenesis is not fully understood.
To prevent the onset of chronic inflammation, a lipid mediator class switch is thought to occur from the initial actions of pro-inflammatory lipid mediators to the anti-inflammatory and pro-resolving actions of lipoxins, resolvins, protectins and maresins (collectively called specialized proresolving mediators (SPMs)). Nanopicogram quantities of different lipid mediators are generated at different times during the evolution of the inflammatory response and these mediators coincide with distinct cellular events. The class switch activates leukocyte translational regulation of the enzymes required to produce pro-resolving lipid mediators (Levy et al. 2001). Each family of these PSMs exert specialized actions, including blocking neutrophil recruitment, promoting the recruitment and activation of monocytes, as well as mediating the nonphlogistic phagocytosis and lymphatic clearance of apoptotic neutrophils by activated macrophages (ie without inducing inflammation) and mediating tissue regeneration. Eventually, through the combined actions of these mediators, the resolution of inflammation is completed and homeostasis is reached (Serhan 2010, Bannenberg & Serhan 2010, Freire & Van Dyke 2013, Serhan et al. 2014).
SPMs are derived from polyunsaturated fatty acids (PUFAs) (Molfino et al. 2017). PUFAs of the ω-3 series are essential nutrients since they cannot be produced by humans (Duvall & Levy 2016) and are primarily found in dietary fish oils (Calder 2013) and in plants (Baker et al. 2016). The ω-3 PUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPAn-3) circulate in the bloodstream after dietary intake and are easily incorporated into cellular membranes in a time- and dose-dependent manner (Calder 2009), as well as being present in inflammatory exudates (Kasuga et al. 2008). They can be mobilised by phospholipase A2 from cellular membranes on injury or infection when they are converted to exudate SPMs (Serhan et al. 2002) to interact with local immune cells (Kasuga et al. 2008). EPA is the source for E-series resolvins while DHA is the source for D-series resolvins, protectins, maresins and sulfido conjugates in tissue regeneration mediators (Serhan et al. 2017). The ω-6 fatty acid arachidonic acid (AA) is the source for lipoxins. ω-3 or ω-6 PUFA docosapentaenoic acids (DPAn-3 and DPAn-6) are the sources of DPA-derived resolvins, protectins and maresins (Vik et al. 2017). Aspirin can also trigger the production of epimeric SPMs via acetylated PTGS2 (prostaglandin G/H synthase, COX2) (Serhan & Chiang 2002). Combinations of oxidation, reduction and hydrolysis can generate numerous SPMs. Electrophilic oxo-derivatives of ω-3 PUFAs are a class of oxidised derivatives that are generated in macrophages and neutrophils by the actions of 5-lipoxygenase, cyclooxygenase-2 and acetylated cyclooxygenase-2, followed by dehydrogenation. Being electrophilic, oxo-derivative SPMs reversibly bind to nucleophilic residues on target proteins, triggering the activation of cytoprotective pathways (Cipollina 2015). The pathways in this section describe the biosynthesis of these SPMs.