Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes.
Pre-clinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation.
SPM join the long list of other physiological agents which tend to limit inflammation (see Inflammation § Resolution) including glucocorticoids, interleukin 10 (an anti-inflammatory cytokine), interleukin 1 receptor antagonist (an inhibitor of the action of pro-inflammatory cytokine, interleukin 1), annexin A1 (an inhibitor of formation of pro-inflammatory metabolites of polyunsaturated fatty acids, and the gaseous resolvins, carbon monoxide (see Carbon monoxide § Physiology), nitric oxide (see Nitric oxide § Biological functions), and hydrogen sulfide (see Hydrogen sulfide §§ Biosynthesis and Signalling role).
[4][5] The absolute as well as relative roles of the SPM along with other physiological anti-inflammatory agents in resolving human inflammatory responses remain to be defined precisely.
[6] Through most of its early period of study, acute inflammatory responses were regarded as self-limiting innate immune system reactions to invading foreign organisms, tissue injuries, and other insults.
These reactions were orchestrated by various soluble signaling agents such as a) foreign organism-derived N-formylated oligopeptide chemotactic factors (e.g. N-formylmethionine-leucyl-phenylalanine); b) complement components C5a and C3a which are chemotactic factors formed during the activation of the host's blood complement system by invading organisms or injured tissues; and c) host cell-derived pro-inflammatory cytokines (e.g. interleukin 1s), host-derived pro-inflammatory chemokines (e.g. CXCL8, CCL2, CCL3, CCL4, CCL5, CCL11, CXCL10), platelet-activating factor, and PUFA metabolites including in particular leukotrienes (e.g. LTB4), hydroxyeicosatetraenoic acids (e.g., 5-HETE, 12-HETE), the hydroxylated heptadecatrienoic acid, 12-HHT, and oxoeicosanoids (e.g. 5-oxo-ETE).
While initially found to have in vitro activity suggesting that they might act as pro-inflammatory agents, Serhan and colleagues and other groups found that the lipoxins as well as a large number of newly discovered metabolites of other PUFA possess primarily if not exclusively anti-inflammatory activities and therefore may be crucial for causing the resolution of inflammation.
In this view, inflammatory responses are not self-limiting but rather limited by the formation of a particular group of PUFA metabolites that counteract the actions of pro-inflammatory signals.
Resolution of the normal inflammatory response, then, may involve switching production of pro-inflammatory to anti-inflammatory PUFA metabolites.
[13][20][21] The following table lists the structural formulae (ETE stands for eicosatetraenoic acid), major activities, and cellular receptor targets (where known).
The following table lists the structural formulae (EPA stands for eicosapentaenoic acid), major activities, and cellular receptor targets (where known).
[23][24][25][30] The following table lists the structural formulae, major activities with citations and cellular receptor targets of D series resolvins.
These three n−3 DPA-derived resolvins have not been defined with respect to the chirality of their hydroxyl residues or the cis–trans isomerism of their double bonds but do possess potent anti-inflammatory activity in animal models and human cells; they also have protective actions in increasing the survival of mice subjected to E. coli sepsis.
[39] The following table lists the structural formulae (DPA stands for docosapentaenoic acid), major activities and cellular receptor targets (where known).
[39][47] The following table lists the structural formulae (DPA stands for docosapentaenoic acid), major activities and cellular receptor targets (where known).
[14][24][25] The following table lists the structural formulae (DHA stands for docosahexaenoic acid), major activities and cellular receptor targets (where known).
[39] The following table lists the structural formulae (DPA stands for docosapentaenoic acid), major activities and cellular receptor targets (where known).
10R,17S-dihydroxy-7Z,11E,13E,15Z,19Z-docosapentaenoic acid (10R,17S-diHDPAEEZ) has been found in inflamed exudates of animal models and possesses in vitro and in vivo anti-inflammatory activity almost as potently as PD1.
Cells metabolize n−6 DPA to 7-hydroxy-DPAn−6, 10,17-dihydroxy-DPAn−6, and 7,17-dihydroxy-DPAn−3; the former two metabolites have been shown to possess anti-inflammatory activity in in vitro and in animal model studies.
Both compounds possess anti-inflammatory activity in vitro; 15-HEDPEA also has tissue-protective effects in mouse models of lung injury and tissue reperfusion.
This negates KEAP1's ability to bind NFE2L2; in consequence, NFE2L2 becomes free to translocate to the nuclease and stimulate the transcription of genes that encode proteins active in detoxifying reactive oxygen species; this effect tends to reduce inflammatory reactions.
[53] In a randomized controlled trial, AT-LXA4 and a comparatively stable analog of LXB4, 15R/S-methyl-LXB4, reduced the severity of eczema in a study of 60 infants.