Specialized pro-resolving mediators

Specialized pro-resolving mediators (SPM, also spelled 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. Prominent members include the resolvins and protectins.

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 the pro-inflammatory cytokine, interleukin 1), annexin A1 (an inhibitor of formation of pro-inflammatory metabolites of PUFAs, 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).

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. Studies suggest that synthetic SPM that are resistant to being metabolically inactivated hold promise of being clinically useful pharmacological tools for preventing and resolving a wide range of pathological inflammatory responses along with the tissue destruction and morbidity that these responses cause. Based on animal model studies, the inflammation-based diseases which may be treated by such metabolically resistant SPM analogs include not only pathological and tissue damaging responses to invading pathogens but also a wide array of pathological conditions in which inflammation is a contributing factor such as allergic inflammatory diseases (e.g. asthma, rhinitis), autoimmune diseases (e.g. rheumatoid arthritis, systemic lupus erythematosus), psoriasis, atherosclerosis disease leading to heart attacks and strokes, type 1 and type 2 diabetes, the metabolic syndrome, and certain dementia syndromes (e.g. Alzheimer's disease, Huntington's disease).

Many of the SPM are metabolites of omega−3 fatty acids and have been proposed to be responsible for the anti-inflammatory actions that are attributed to omega−3 fatty acid-rich diets.

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). These agents functioned as pro-inflammatory signals by increasing the permeability of local blood vessels; activating tissue-bound pro-inflammatory cells such as mast cells, and macrophages; and attracting to nascent inflammatory sites and activating circulating neutrophils, monocytes, eosinophils, gamma delta T cells, and natural killer T cells. The cited cells then proceeded to neutralize invading organisms, limit tissue injury, and initiate tissue repair. Hence, the classic inflammatory response was viewed as fully regulated by the soluble signaling agents. That is, the agents formed, orchestrated an inflammatory cell response, but then dissipated to allow resolution of the response. In 1974, however, Charles N. Serhan, Mats Hamberg and Bengt Samuelsson, discovered that human neutrophils metabolize arachidonic acid to two novel products that contain 3 hydroxyl residues and 4 double bonds viz., 5,6,15-trihydroxy-7,9,11,13-icosatetraenoic acid and 5,14,15-trihydroxy-6,8,10,12-icosatetraenoic acid. These products are now termed lipoxin A4 and B4, respectively. 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. Later, these PUFA metabolites were classified together and termed specialized pro-resolving mediators (i.e. SPM).

The production and activities of the SPM suggest a new view of inflammation wherein the initial response to foreign organisms, tissue injury, or other insults involves numerous soluble cell signaling molecules that not only recruit various cell types to promote inflammation but concurrently cause these cells to produce SPM which feed back on their parent and other cells to dampen their pro-inflammatory activity and to promote repair. Resolution of an inflammatory response is thus an active rather than self-limiting process which is set into motion at least in part by the initiating pro-inflammatory mediators (e.g. prostaglandin E2 and prostaglandin D2) which instruct relevant cells to produce SPM and to assume a more anti-inflammatory phenotype. Resolution of the normal inflammatory response, then, may involve switching production of pro-inflammatory to anti-inflammatory PUFA metabolites. Excessive inflammatory responses to insult as well as many pathological inflammatory responses that contribute to diverse diseases such as atherosclerosis, obesity, diabetes, Alzheimer's disease, inflammatory bowel disease, etc. (see Inflammation § Disorders) may reflect, in part, a failure in this class switching. Diseases caused or worsened by non-adaptive inflammatory responses may by amenable to treatment with SPM or synthetic SPM which, unlike natural SPM, resist in vivo metabolic inactivation. The SPM possess overlapping activities which work to resolve inflammation. SPMs (typically more than one for each listed action) have the following anti-inflammatory activities on the indicated cell types as defined in animal and human model studies:

SPMs also stimulate anti-inflammatory and tissue reparative types of responses in epithelium cells, endothelium cells, fibroblasts, smooth muscle cells, osteoclasts, osteoblasts, goblet cells, and kidney podocytes as well as activate the heme oxygenase system of cells thereby increasing the production of the tissue-protective gaso-transmitter, carbon monoxide (see Carbon monoxide § Physiology), in inflamed tissues.

SPM are metabolites of arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or n−3 DPA (i.e. 7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid or clupanodonic acid); these metabolites are termed lipoxins (Lx), resolvins (Rv), protectins (PD) (also termed neuroprotectins [NP]), and maresins (MaR). EPA, DHA, and n−3 DPA are n−3 fatty acids; their conversions to SPM are proposed to be one mechanism by which n−3 fatty acids may ameliorate inflammatory diseases (see Omega−3 fatty acid § Inflammation). SPM act, at least in part, by either activating or inhibiting cells through binding to and thereby activating or inhibiting the activation of specific cellular receptors.