Specialized pro-resolving mediators

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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. [1] [2] [3] Prominent members include the resolvins and protectins.

Contents

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. However, 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). [1] [2] [3]

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. [6]

History

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. [7] 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. [8] [9] 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. [10] Later, these PUFA metabolites were classified together and termed specialized pro-resolving mediators (i.e. SPM). [11]

Inflammation

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. [12] [2] [13] [14] 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: [1] [15] [16] [17]

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 [1] 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. [18]

Biochemistry

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). [19] 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.

Lipoxins

Human cells synthesize LxA4 and LxB4 by serially metabolizing arachidonic acid (5Z,8Z,11Z,14Z-eicosatetraenoic acid) with a) ALOX15 (or possibly ALOX15B) followed by ALOX5; b) ALOX5 followed by ALOX15 (or possibly ALOX15B); or c) ALOX5 followed by ALOX12. Cells and, indeed, humans treated with aspirin form the 15R-hydroxy epimer lipoxins of these two 15S-lipoxins viz., 15-epi-LXA4 and 15-epi-LXB4, through a pathway that involves ALOX5 followed by aspirin-treated cyclooxygenase-2 (COX-2). Aspirin-treated COX-2, while inactive in metabolizing arachidonic acid to prostanoids, metabolizes this PUFA to 15R-hydroperoxy-eicosatetraenoic acid whereas the ALOX15 (or ALOX15B) pathway metabolizes arachidonic acid to 15S-hydroperoxy-eicosatetraenoic acid. The two aspirin-triggered lipoxins (AT-lipoxins) or epi-lipoxins differ structurally from LxA4 and LxB4 only in the S versus R chirality of their 15-hydroxyl residue. Numerous studies have found that these metabolites have potent anti-inflammatory activity in vitro and in animal models and in humans may stimulate cells by binding to certain receptors on these cells. [13] [20] [21] The following table lists the structural formulae (ETE stands for eicosatetraenoic acid), major activities, and cellular receptor targets (where known).

Trivial nameFormulaActivitiesReceptor(s)
LxA45S,6R,15S-trihydroxy-7E,9E,11Z,13E-ETEAnti-inflammatory, blocks pain perception [2] [20] Stimulates FPR2, AHR [20] [22]
LxB45S,14R,15S-trihydroxy-6E,8Z,10E,12E-ETEAnti-inflammatory, blocks pain perception [2] [20]  ?
15-epi-LxA4 (or AT-LxA4)5S,6R,15R-trihydroxy-7E,9E,11Z,13E-ETEAnti-inflammatory, blocks pain perception [2] [20] stimulates FPR2 [20]
15-epi-LxB4 (or AT-LxB4)5S,14R,15R-trihydroxy-6E,8Z,10E,12E-ETEAnti-inflammatory, blocks pain perception [2] [20]  ?

Resolvins

Resolvins are metabolites of omega−3 fatty acids, EPA, DHA, and 7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid (n−3 DPA). All three of these omega−3 fatty acids are abundant in salt water fish, fish oils, and other seafood. [19] n−3 DPA (also termed clupanodonic acid) is to be distinguished from its n−6 DPA isomer, i.e. 4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid, also termed osbond acid.

EPA-derived resolvins

Cells metabolize EPA (5Z,8Z,11Z,14Z,17Z-eicosapentaenoic acid) by a cytochrome P450 monooxygenase(s) (in infected tissues a bacterial cytochrome P450 may supply this activity) or aspirin-treated cyclooxygenase-2 to 18R-hydroperoxy-EPA which is then reduced to 18R-hydroxy-EPA and further metabolized by ALOX5 to 5S-hydroperoxy-18R-hydroxy-EPA; the later product may be reduced to its 5,18-dihydroxy product, RvE2, or converted to its 5,6-epoxide and then acted on by an epoxide hydrolase to form a 5,12,18-trihydroxy derivative, RvE1. In vitro, ALOX5 can convert 18S-HETE to the 18S analog of RvE1 termed 18S-RvE1. 18R-HETE or 18S-HETE may also be metabolized by ALOX15 to its 17S-hydroperoxy and then reduced to its 17S-hydroxy product, Rv3. Rv3, as detected in in vitro studies, is a dihydroxy mixture of 18S-dihydroxy (i.e. 18S-RvE3) and 18R-dihydroxy (i.e. 18R-RvE3) isomers, both of which, similar to the other aforementioned metabolites possess potent SPM activity in in vitro and/or animal models. [24] [25] [26] In vitro studies find that ALOX5 can convert 18S-hydroperoxy-EPA to the 18S-hydroxy analog of RvE2 termed 18S-RvE2. 18S-RvE2, however has little or no SPM activity [26] and is therefore not considered to be a SPM here. The following table lists the structural formulae (EPA stands for eicosapentaenoic acid), major activities, and cellular receptor targets (where known).

Trivial nameFormulaActivitiesReceptor(s)
RvE15S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-EPAAnti-inflammatory, blocks pain perception [1] [27] stimulates CMKLR1, receptor antagonist of BLT, inhibits activation of TRPV1, TRPV3, NMDAR, and TNFR receptors [1] [17] [24]
18S-RvE15S,12R,18S-trihydroxy-6Z,8E,10E,14Z,16E-EPAAnti-inflammatory, blocks pain perception [1] [27] stimulates CMKLR1, receptor antagonist of BLT [24] [28]
RvE25S,18R-dihydroxy-6E,8Z,11Z,14Z,16E-EPAAnti-inflammatory [1] partial receptor agonist of CMKLR1, receptor antagonist of BLT [24] [29]
RvE317R,18R/S-dihydroxy-5Z,8Z,11Z,13E,15E-EPAAnti-inflammatory [1]  ?
  • CMKLR1 (chemokine receptor-like 1), also termed the ChemR23 or E series resolvin receptor (ERV), is expressed on inflammation-regulating NK cells, macrophages, dendritic cells, and innate lymphoid cells as well as on epithelial cells and in brain, kidney, cardiovascular, gastrointestinal, and myeloid tissues; BLT is the receptor for LTB4 along with certain other pro-inflammatory agents and is expressed on human neutrophils, eosinophils, monocytes, macrophages, T cells, mast cells, and dendritic cells as well as in vascular tissue; GPR32 (also termed the RvD1 receptor or DRV1) is expressed on human inflammation-regulating neutrophils, lymphocytes, monocytes, macrophages, and vascular tissue. TRPV1 and TRPV3 are expressed on neurons and supporting cells, principally of the peripheral nervous system, that are involved in the sensory perception of pain; the NMDA receptor is a glutamate receptor and ion channel protein involved in controlling synaptic plasticity and memory. [1] [23] [24]

DHA-derived resolvins

Cells metabolize DHA (4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid) by either ALOX15 or a cytochrome P450 monooxygenase(s) (bacteria may supply the cytochrome P450 activity in infected tissues) or aspirin-treated cyclooxygenase-2 to 17S-hydroperoxy-DHA which is reduced to 17S-hydroxy-DHA. ALOX5 metabolizes this intermediate to a) 7S-hydroperoxy,17S-hydroxy-DHA which is then reduced to its 7S,17S-dihydroxy analog, RvD5; b) 4S-hydroperoxy,17S-hydroxy-DHA which is reduced to its 4S,17S-dihydroxy analog, RvD6; c) 7S,8S-epoxy-17S-DHA which is then hydrolyzed to 7,8,17-trihydroxy and 7,16,17-trihydorxy products, RvD1 and RvD2, respectively; and d) 4S,5S-epoxy-17S-DHA which is then hydrolyzed to 4,11,17-trihydroxy and 4,5,17-trihydroxy products, RvD3 and RvD4, respectively. These six RvDs possess a 17S-hydroxy residue; however, if aspirin-treated cyclooxygenase-2 is the initiating enzyme, they contain a 17R-hydroxy residue and are termed 17R-RvDs, aspirin-triggered-RvDs, or AT-RvDs 1 thru 6. In certain cases, the final structures of these AT-RvDs is assumed by analogy to the structures of their RvD counterparts. Studies have found that most (and presumably all) of these metabolites have potent anti-inflammatory activity in vitro and/or in animal models. [23] [24] [25] [30] The following table lists the structural formulae, major activities with citations and cellular receptor targets of D series resolvins.

Trivial nameFormulaActivitiesReceptor(s)
RvD17S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-DHAAnti-inflammatory, blocks pain perception [1] [31] stimulates GPR32, FPR2, inhibits activation of TRPV3, TRPV4, TRPA1 [24]
RvD27S,16R,17S-trihydroxy-4Z,8E,10Z,12E,14E,19Z-DHAAnti-inflammatory, blocks pain perception, [1] [32] increases survival after sepsis [33] stimulates GPR32, GPR18, FPR2, inhibits activation of TRPV1 and TRPA1 [17] [18]
RvD34S,11R,17S-trihydroxy-5Z,7E,9E,13Z,15E,19Z-DHAAnti-inflammatory [1] stimulates GPR32 [24]
RvD44S,5R,17S-trihydroxy-6E,8E,10Z,13Z,15E,19Z-DHA ? ?
RvD57S,17S-dihydroxy-4Z,8E,10Z,13Z,15E,19Z-DHAAnti-inflammatory [1] stimulates GPR32 [24]
RvD64S,17S-dihydroxy-5E,7Z,10Z,13Z,15E,19Z-DHA ? ?
17R-RvD1 (AT-RvD1)7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-DHAAnti-inflammatory, blocks pain perception [1] [31] stimulates FPR2, GPR32, inhibits activation of TRPV3, TRPV4, and TNFR [17] [24]
17R-RvD2 (AT-RvD2)7S,16R,17R-trihydroxy-4Z,8E,10Z,12E,14E,19Z-DHA ? ?
17R-RvD3 (AT-RvD3)4S,11R,17R-trihydroxy-5Z,7E,9E,13Z,15E,19Z-DHAAnti-inflammatory [1] stimulates GPR32 [24]
17R-RvD4 (AT-RvD4)4S,5R,17R-trihydroxy-6E,8E,10Z,13Z,15E,19Z-DHA ? ?
17R-RvD5 (AT-RvD5)7S,17R-dihydroxy-4Z,8E,10Z,13Z,15E,19Z-DHA ? ?
17R-RvD6 (AT-RvD6)4S,17R-dihydroxy-5E,7Z,10Z,13Z,15E,19Z-DHA ? ?
  • The distribution and major functions of GPR32, FPR2, TRPV1, and TRPV3 are given in the above EPA-derived resolvins section; TRPA1 is a chemosensor ion channel located on the plasma membrane of many human cell types; TRPV4, also termed the vanilloid-receptor related osmotically activated channel (VR-OAC) and OSM9-like transient receptor potential channel member 4 (OTRPC4)2], is involved in multiple physiologic functions and dysfunctions. With respect to the SPMS, both receptors mediate the perception of various forms of inflammation-triggered pain. [1] [24]
  • The initial product of 15-lipoxygenase attack on DHA is 17S-hydroperoxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid (17-HpDHA) which may then be rapidly reduced by a cellular glutathione peroxidase to 17S-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid (17-HDHA). 17-HDHA has potent anti-inflammatory activity and has been classified as a SPM although not a resolvin. [34] [35] Similarly, 14S,20R-dihyrdoxy-4Z,7Z,10Z,12E,16Z,18E-docosahexaenoic acid, while not yet assigned a RvD number, qualifies as a RvD-related SPM. It is a DHA metabolite made by mouse eosinophils, detected in the peritoneal fluid of mice undergoing experimental peritonitis, and possessing the ability to inhibit the influx of leukocytes into the peritoneum of the mice. [25] [36] Finally, two resolvin sulfido-conjugates (8-glutathionyl,7,17-dihydroxy-4Z,9,11,13Z,15E,19Z-docosahexaenoic acid and 8-cysteinylglycinyl,7,17-dihydroxy-4Z,9,11,13Z,15E,19Z-docosahexaenoic acid) have been shown to be formed from their 7,17-dihydroxy precursor by cells in vitro, to accelerate regeneration of experimental injuries in planaria worms, and to have potent anti-inflammatory activity in various in vitro model systems. [37]

n−3 DPA-derived resolvins

n−3 DPA (i.e. 7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid)-derived resolvins are recently identified SPM. In the model system used to identify them, human platelets pretreated with aspirin to form acetylated COX-2 or with the statin, atorvastatin, to form S-nitrosylated COX-2, thereby modify this enzyme's activity. The modified enzyme metabolizes n−3 DPA to a 13R-hydroperoxy-n−3 DPA intermediate which is passed over to nearby human neutrophils; these cells then metabolize the intermediate to four poly-hydroxyl metabolites termed resolvin T1 (RvT1), RvT2, RvT3, and RvT4. These T series resolvins also form in mice undergoing experimental inflammatory responses and have potent in vitro and in vivo anti-inflammatory activity; they are particularly effective in reducing the systemic inflammation as well as increasing the survival of mice injected with lethal doses of E. coli bacteria. [25] [38] [39] Another set of newly described n−3 DPA resolvins, RvD1n−3, RvD2n−3, and RvD5n−3, have been named based on their presumed structural analogies to the DHA-derived resolvins RvD1, RvD2, and RvD5, respectively. 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).

Trivial nameFormulaActivitiesReceptor(s)
RvT17S,13R,20S-trihydroxy-8E,10Z,14E,16Z,18E-DPA [40] [41] Anti-inflammatory [25] [38]  ?
RvT27S,12R,13S-trihydroxy-8Z,10E,14E,16Z,19Z-DPA [40] [41] Anti-inflammatory [25] [38]  ?
RvT37S,8R,13S-trihydroxy-9E,11E,14E,16Z,19Z-DPA [41] Anti-inflammatory [25] [38]  ?
RvT47S,13R-dihydroxy-8E,10Z,14E,16Z,19Z-DPA [40] [41] Anti-inflammatory [25] [38]  ?
RvD1n−37S,8R,17S-trihydroxy-9E,11E,13Z,15E,19Z-DPA [40] [42] Anti-inflammatory [39]  ?
RvD2n−37S,16R,17S-trihydroxy-8E,10Z,12E,14E,19Z-DPA [40] Anti-inflammatory [39]  ?
RvD5n−37S,17S-dihydroxy-8E,10Z,13Z,15E,19Z-DPA [40] [42] Anti-inflammatory [39] GPR101 [42]

Protectins/neuroprotectins

DHA-derived protectins/neuroprotectins

Cells metabolize DHA by either ALOX15, by a bacterial or mammalian cytochrome P450 monooxygenase (Cyp1a1, Cyp1a2, or Cyp1b1 in mice; see CYP450 §§  CYP families in humans ​ and P450s in other species) or by aspirin-treated cyclooxygenase-2 to 17S-hydroperoxy or 17R-hydroperoxy intermediates (see previous subsection); this intermediate is then converted to a 16S,17S-epoxide which is then hydrolyzed (probably by a soluble epoxide hydrolase to protectin D1 (PD1, also termed neuroprotectin D1 [NPD1] when formed in neural tissue). [2] PDX is formed by the metabolism of DHA by two serial lipoxygenases, probably a 15-lipoxygenase and ALOX12. 22-Hydroxy-PD1 (also termed 22-hydroxy-NPD1) is formed by the omega oxidation of PD1 probably by an unidentified cytochrome P450 enzyme. While omega-oxidation products of most bioactive PUFA metabolites are far weaker than their precursors, 22-hydroxy-PD1 is as potent as PD1 in inflammatory assays. Aspirin-triggered-PD1 (AT-PD1 or AP-NPD1) is the 17R-hydroxyl diastereomer of PD1 formed by the initial metabolism of DHA by aspirin-treated COX-2 or possibly a cytochrome P450 enzyme to 17R-hydroxy-DHA and its subsequent metabolism possibly in manner similar to that which forms PD1. 10-Epi-PD1 (ent-AT-NPD1), the 10S-hydroxy diastereomer of PD1, has been detected in small amounts in human neutrophils. While its in vivo synthetic pathway has not been defined, 10-epi-PD1 has anti-inflammatory activity. [25] [43] The following table lists the structural formulae (DHA stands for docosahexaenoic acid), major activities, cellular receptor targets (where known), and Wikipedia pages giving further information on the activity and syntheses.

Trivial nameFormulaActivitiesReceptor(s)See Wikipedia pages
PD1 (NPD1)10R,17S-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-DHAanti-inflammatory, nerve protection/regeneration, blocks pain perception [44] inhibits the activation of TRPV1 [17] Neuroprotectin D1
PDX10S,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-DHAanti-inflammatory, inhibits platelet activation [45]  ? Neuroprotectin D1 § Protectin DX and Dihydroxy-E,Z,E-PUFA
22-hydroxy-PD110R,17S,22-trihydroxy-4Z,7Z,11E,13E,15Z,19Z-DHAanti-inflammatory [44]  ? Neuroprotectin D1 § Protectin DX and Dihydroxy-E,Z,E-PUFA
17-epi-PD1 (AT-PD1)10R,17R-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-DHAanti-inflammatory [14]  ? Neuroprotectin D1 § Aspirin-triggered PD1
10-epi-PD1 (ent-AT-NPD1)10S,17S-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-DHAanti-inflammatory [44]  ? Neuroprotectin D1 § 10-epi-PD1
  • The TRPV1 receptor is discussed in the EPA-derived resolvin section.
  • While not yet given trivial names, certain isomers of the protectins also prove to have SPM activity: the 13Z cis–trans isomer of 10-epi-PD1, 10S,17S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-DHA, is a relatively abundant metabolite compared to PD1 detected in the peritoneal fluid from a mouse model of peritonitis (although not detected in stimulated leukocytes) and has moderately potent anti-inflammatory activity in this model; 10R,17S-dihydroxy-4Z,7Z,11E,13E,15E,19Z-DHA, is a prominent metabolite detected in stimulated leukocytes, not detected the mouse peritonitis model, and has modest anti-inflammatory activity in the latter model; and 10S,17S-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-DHA, while not detected by in the mouse model of peritonitis or stimulated leukocytes, is more potent than even PD1 in inhibiting peritonitis in the mouse model. [46] In addition to these compounds, two protectin sulfido-conjugates (16-glutathionyl,17-hydroxy-4Z,7Z,10,12,14,19Z-docosahexaenoic acid and 16-cysteinylglycinyl,17-hydroxy-4Z,7Z,10,12,14,19Z-docosahexaenoic acid) form in vitro, accelerate regeneration of injured planaria worms, and have potent anti-inflammatory activity in in vitro model systems. [37]

n−3 DPA-derived protectins/neuroprotectins

n−3 DPA-derived protectins with structural similarities to PD1 and PD2 have been described, determined to be formed in vitro and in animal models, and termed PD1n−3 and PD2n−3, respectively. These products are presumed to be formed in mammals by the metabolism of n−3 DPA by an unidentified 15-lipoxygenase activity to 16,17-epoxide intermediate and the subsequent conversion of this intermediate to the di-hydroxyl products PD1n−3 and PD2n−3. PD1n−3 has anti-inflammatory activity in a mouse model of peritonitis; PD2n−3 has anti-inflammatory activity in an in vitro model. [39] [47] The following table lists the structural formulae (DPA stands for docosapentaenoic acid), major activities and cellular receptor targets (where known).

Trivial nameFormulaActivitiesReceptor(s)
PD1n−310,17-dihydroxy-7,11,13,15,19-DPAanti-inflammatory [39]  ?
PD2n−316,17-dihydroxy-7,10,12,14,19-DPAanti-inflammatory [47]  ?

Maresins

DHA-derived maresins

Cells metabolize DHA by ALOX12, other lipoxygenase, (12/15-lipoxygenase in mice), or an unidentified pathway to a 13S,14S-epoxide-4Z,7Z,9E,11E,16Z,19Z-DHA intermediate (13S,14S-epoxy-maresin MaR) and then hydrolyze this intermediate by an epoxide hydrolase activity (which ALOX 12 and mouse 12/15-lipoxygenase possess) to MaR1 and MaR2. During this metabolism, cells also form 7-epi-Mar1, i.e. the 7S-12E isomer of Mar1, as well as the 14S-hydroxy and 14R-hydroxy metabolites of DHA. The latter hydroxy metabolites can be converted by an unidentified cytochrome P450 enzyme to maresin like-1 (Mar-L1) and Mar-L2 by omega oxidation; alternatively, DHA may be first metabolized to 22-hydroxy-DHA by CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP2E1, or CYP3A4 and then metabolized through the cited epoxide-forming pathways to Mar-L1 and MaR-L2. Studies have found that these metabolites have potent anti-inflammatory activity in vitro and in animal models. [14] [24] [25] The following table lists the structural formulae (DHA stands for docosahexaenoic acid), major activities and cellular receptor targets (where known).

Trivial nameFormulaActivitiesReceptor(s)
MaR17R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-DHAanti-inflammatory, tissue regeneration, blocks pain perception [14] Inhibits the activation of the vanilloid receptor TRPV1 and TRPA1 [17] [24]
MaR213R,14S-dihydroxy-4Z,7Z,9E,11E,16Z,19Z-DHAanti-inflammatory [14]  ?
7-epi-MaR17S,14S-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-DHAanti-inflammatory [44]  ?
MaR-L114S,22-dihydroxy-4Z,7Z,10Z,12E,16Z,19Z-DHAanti-inflammatory [44] [48]  ?
MaR-L214R,22-dihydroxy-4Z,7Z,10Z,12E,16Z,19Z-DHAanti-inflammatory [44] [48]  ?
  • Studies in mice detected a series of R/S 14,21-dihydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid isomers (14R,21R-diHDHA, 14R,21S-diHDHA, 14S,21R-diHDHA, and 14S,21S-diHDHA) form in inflamed tissues and in cultures of murine macrophages; the 14R,21-diHDHA and 14S,21-diHDHA isomers promoted wound healing in mouse models of inflammation. [14] [49]
  • Mouse eosinophils metabolize DHA to a maresin-like product, 14S,20R-dihydroxy-4Z,7Z,10Z,12E,16Z,18Z-docosahexaenoic acid. This product, as well as its 14,S,20S isomer possesses potent anti-inflammatory activity in mice. [25]
  • The TRPV1 receptor is discussed in the EPA-derived resolvin section; the TRPA1 receptor is discussed in the DHA-derived resolvin section.

n−3 DPA-derived maresins

n−3 DPA-derived maresins are presumed to be formed in mammals by metabolism of n−3 DPA by an undefined 12-lipoxygenase activity to a 14-hydroperoxy-DPA intermediated and the subsequent conversion of this intermediate to di-hydroxyl products which have been termed MaR1n−3, MaR2n−3, and MaR3n−3 based on their structural analogies to MaR1, MaR2, and MaR3, respectively. MaR1n−3 and MaR2n−3 have been found to possess anti-inflammatory activity in in vitro assays of human neutrophil function. These n−3 DPA-derived maresins have not been defined with respect to the chirality of their hydroxyl residues or the cis–trans isomerism of their double bonds. [39] The following table lists the structural formulae (DPA stands for docosapentaenoic acid), major activities and cellular receptor targets (where known).

Trivial nameFormula [47] ActivitiesReceptor(s)
MaR1n−37S,14S-dihydroxy-8E,10E,12Z,16Z,19Z-DPAanti-inflammatory [39] [44]  ?
MaR2n−313,14-dihydroxy-7Z,9E,11E,16Z,19Z-DPAanti-inflammatory [39]  ?
MaR3n−314,21-dihydroxy-7Z,10Z,12E,16Z,19Z-DPA ? ?

Other PUFA metabolites with SPM-like activity

The following PUFA metabolites, while not yet formally classified as SPM, have been recently described and determined to have anti-inflammatory activity.

n−3 DPA metabolites

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. [44]

n−6-DPA metabolites

n−6 DPA (i.e. 4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid or osbond acid) is an isomer of n−3 DPA (clupanodonic acid) differing from the latter fatty acid only in the location of its 5 double bonds. 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. [39]

Oxo-DHA and oxo-DPA metabolites

Cells metabolize DHA and n−3 DPA by COX-2 to 13-hydroxy-DHA and 13-hydroxy-DPAn−3 products and by aspirin-treated COX-2 to 17-hydroxy-DHA and 17-hydroxy-DPAn−3 products and may then oxidize these products to their corresponding oxo (i.e. ketone) derivatives, 13-oxo-DHA (also termed electrophilic fatty acid oxo derivative or EFOX-D6), 13-oxo-DPAn−3 (EFOX-D5), 17-oxo-DHA (17-EFOX-D6), and 17-oxo-DPAn−3 (17-EFOX-D3). These oxo metabolites directly activate the nuclear receptor peroxisome proliferator-activated receptor gamma and possess anti-inflammatory activity as assesses in in vitro systems. [39]

Docosahexaenoyl ethanolamide metabolites

DHA ethanolamide ester (the DHA analog of arachindonyl ethanolamide (i.e. anandamide) is metabolized to 10,17-dihydroxydocosahexaenoyl ethanolamide (10,17-diHDHEA) and/or 15-hydroxy-16(17)-epoxy-docosapentaenoyl ethanolamide (15-HEDPEA) by mouse brain tissue and human neutrophils. Both compounds possess anti-inflammatory activity in vitro; 15-HEDPEA also has tissue-protective effects in mouse models of lung injury and tissue reperfusion. Like anandamide, both compounds activated the cannabinoid receptor. [50] [51]

Prostaglandins and isoprostanes

PUFA derivatives containing a cyclopentenone structure are chemically reactive and can form adducts with various tissue targets, particularly proteins. Certain of these PUFA-cyclopentenones bind to the sulfur residues in the KEAP1 component of the KEAP1-NFE2L2 protein complex in the cytosol of cells. 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. PUFA-cyclopentenones may likewise react with the IKK2 component of the cytosolic IKK2-NFκB protein complex thereby inhibiting NFκB from stimulating the transcription of genes that encode various pro-inflammatory proteins. One or both of these mechanisms appears to contribute to the ability of certain highly reactive PUFA-cyclopenetenones to exhibit SPM activity. The PUFA-cyclopentenones include two prostaglandins, (PG) Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2, and two isoprostanes, 5,6-epoxyisoprostane E2 and 5,6-epoxyisoprostane A2. Both PGJ2's are arachidonic acid-derived metabolites made by cyclooxygenases, primarily COX-2, which is induced in many cell types during inflammation. Both isoprostanes form non-enzymatically as a result the attack on the arachidonic acid bond to cellular phospholipids by reactive oxygen species; they are then release from the phospholipids to become free in attacking their target proteins. All four products have been shown to form and possess SPM activity in various in vitro studies of human and animal tissue as well as in in vivo studies of animal models of inflammation; they have been termed pro-resolving mediators of inflammation [52]

Gene manipulation studies

Mice made deficient in their 12/15-lipoxygenase gene (Alox15) exhibit a prolonged inflammatory response along with various other aspects of a pathologically enhanced inflammatory response in experimental models of cornea injury, airway inflammation, and peritonitis. These mice also show an accelerated rate of progression of atherosclerosis whereas mice made to overexpress 12/15-lipoxygenase exhibit a delayed rate of atherosclerosis development. Alox15 overexpressing rabbits exhibited reduced tissue destruction and bone loss in a model of periodontitis. [2] Similarly, Alox5 deficient mice exhibit a worsened inflammatory component, failure to resolve, and/or decrease in survival in experimental models of respiratory syncytial virus disease, Lyme disease, Toxoplasma gondii disease, and corneal injury. [2] These studies indicate that the suppression of inflammation is a major function of 12/15-lipoxygenase and Alox5 along with the SPMs they make in at least certain rodent experimental inflammation models; although these rodent lipoxygenases differ from human ALOX15 and ALOX5 in the profile of the PUFA metabolites that they make as well as various other parameters (e.g. tissue distribution), these genetic studies allow that human ALOX15, ALOX5, and the SPMs they make may play a similar anti-inflammatory functions in humans.

Concurrent knockout of the three members of the CYP1 family of cytochrome P450 enzymes in mice, i.e. Cyp1a1, Cyp1a2, and Cyp1b1, caused an increase in the recruitment of neutrophils to the peritoneum in mice undergoing experimental peritonitis; these triple knockout mice also exhibited an increase in the peritoneal fluid LTB4 level and decreases in the levels of peritoneal fluid NPD1 as well as the precursors to various SPMs including 5-hydroxyeicosatetraenoic acid, 15-hydroxyeicosatetraenoic acid, 18-hydroxyeicosapentaenoic acid, 17-hydroxydocosahexaenoic acid, and 14-hydroxydocosahexaenoic. These results support the notion that Cyp1 enzymes contribute to the production of certain SPMs and inflammatory responses in mice; CYP1 enzymes may therefore play a similar role in humans. [53]

Clinical studies

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. [54] [55] A synthetic analog of ReV1 is in clinical phase III testing (see Phases of clinical research) for the treatment of the inflammation-based dry eye syndrome; along with this study, other clinical trials (NCT01639846, NCT01675570, NCT00799552 and NCT02329743) using an RvE1 analogue to treat various ocular conditions are underway. [16] RvE1, Mar1, and NPD1 are in clinical development studies for the treatment of neurodegenerative diseases and hearing loss. [2] And, in a single study, inhaled LXA4 decreased LTC4-initiated bronchoprovocation in patients with asthma. [16]

See also

Related Research Articles

<span class="mw-page-title-main">Eicosanoid</span> Class of compounds

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Some eicosanoids, such as prostaglandins, may also have endocrine roles as hormones to influence the function of distant cells.

<span class="mw-page-title-main">Lipoxin</span> Acronym for lipoxygenase interaction product

A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs: the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4 respectively.

<span class="mw-page-title-main">Resolvin</span> Class of chemical compounds

Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as from two isomers of docosapentaenoic acid (DPA), one omega-3 and one omega-6 fatty acid. As autacoids similar to hormones acting on local tissues, resolvins are under preliminary research for their involvement in promoting restoration of normal cellular function following the inflammation that occurs after tissue injury. Resolvins belong to a class of polyunsaturated fatty acid (PUFA) metabolites termed specialized proresolving mediators (SPMs).

Docosapentaenoic acid (DPA) designates any straight open chain polyunsaturated fatty acid (PUFA) which contains 22 carbons and 5 double bonds. DPA is primarily used to designate two isomers, all-cis-4,7,10,13,16-docosapentaenoic acid and all-cis-7,10,13,16,19-docosapentaenoic acid. They are also commonly termed n-6 DPA and n-3 DPA, respectively; these designations describe the position of the double bond being 6 or 3 carbons closest to the (omega) carbon at the methyl end of the molecule and is based on the biologically important difference that n-6 and n-3 PUFA are separate PUFA classes, i.e. the omega-6 fatty acids and omega-3 fatty acids, respectively. Mammals, including humans, can not interconvert these two classes and therefore must obtain dietary essential PUFA fatty acids from both classes in order to maintain normal health.

<span class="mw-page-title-main">Hepoxilin</span> Chemical compound

Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoid derived from acid the (PUFA), arachidonic acid. A second group of less well studied hepoxilins, HxA4, HxB4, and their non-enzymatically formed isomers are nonclassical eicosanoids derived from the PUFA, eicosapentaenoic acid. Recently, 14,15-HxA3 and 14,15-HxB3 have been defined as arachidonic acid derivatives that are produced by a different metabolic pathway than HxA3, HxB3, HxA4, or HxB4 and differ from the aforementioned hepoxilins in the positions of their hydroxyl and epoxide residues. Finally, hepoxilin-like products of two other PUFAs, docosahexaenoic acid and linoleic acid, have been described. All of these epoxyalcohol metabolites are at least somewhat unstable and are readily enzymatically or non-enzymatically to their corresponding trihydroxy counterparts, the trioxilins (TrX). HxA3 and HxB3, in particular, are being rapidly metabolized to TrXA3, TrXB3, and TrXC3. Hepoxilins have various biological activities in animal models and/or cultured mammalian tissues and cells. The TrX metabolites of HxA3 and HxB3 have less or no activity in most of the systems studied but in some systems retain the activity of their precursor hepoxilins. Based on these studies, it has been proposed that the hepoxilins and trioxilins function in human physiology and pathology by, for example, promoting inflammation responses and dilating arteries to regulate regional blood flow and blood pressure.

Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and therefore are short-lived. Accordingly, the eicosanoid-receptor interaction is typically limited to a local interaction: cells, upon stimulation, metabolize arachidonic acid to an eicosanoid which then binds cognate receptors on either its parent cell or on nearby cells to trigger functional responses within a restricted tissue area, e.g. an inflammatory response to an invading pathogen. In some cases, however, the synthesized eicosanoid travels through the blood to trigger systemic or coordinated tissue responses, e.g. prostaglandin (PG) E2 released locally travels to the hypothalamus to trigger a febrile reaction. An example of a non-GPCR receptor that binds many eicosanoids is the PPAR-γ nuclear receptor.

Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme that in humans is encoded by the ALOX5 gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase family of enzymes. It transforms essential fatty acids (EFA) substrates into leukotrienes as well as a wide range of other biologically active products. ALOX5 is a current target for pharmaceutical intervention in a number of diseases.

In biochemistry, docosanoids are signaling molecules made by the metabolism of twenty-two-carbon fatty acids (EFAs), especially the omega-3 fatty acid, docosahexaenoic acid (DHA) by lipoxygenase, cyclooxygenase, and cytochrome P450 enzymes. Other docosanoids are metabolites of n-3 docosapentaenoic acid (DPA), n-6 DPA, and docosatetraenoic acid. Prominent docosanoid metabolites of DPA and n-3 DHA are members of the specialized pro-resolving mediators class of polyunsaturated fatty acid metabolites that possess potent anti-inflammation, tissue healing, and other activities.

<span class="mw-page-title-main">ALOX15</span> Lipoxygenase found in humans

ALOX15 is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products. ▼ Gene Function

<span class="mw-page-title-main">ALOX12</span> Protein-coding gene in the species Homo sapiens

ALOX12, also known as arachidonate 12-lipoxygenase, 12-lipoxygenase, 12S-Lipoxygenase, 12-LOX, and 12S-LOX is a lipoxygenase-type enzyme that in humans is encoded by the ALOX12 gene which is located along with other lipoyxgenases on chromosome 17p13.3. ALOX12 is 75 kilodalton protein composed of 663 amino acids.

<span class="mw-page-title-main">Formyl peptide receptor 2</span> Protein-coding gene in the species Homo sapiens

N-formyl peptide receptor 2 (FPR2) is a G-protein coupled receptor (GPCR) located on the surface of many cell types of various animal species. The human receptor protein is encoded by the FPR2 gene and is activated to regulate cell function by binding any one of a wide variety of ligands including not only certain N-Formylmethionine-containing oligopeptides such as N-Formylmethionine-leucyl-phenylalanine (FMLP) but also the polyunsaturated fatty acid metabolite of arachidonic acid, lipoxin A4 (LXA4). Because of its interaction with lipoxin A4, FPR2 is also commonly named the ALX/FPR2 or just ALX receptor.

<span class="mw-page-title-main">NAGly receptor</span> Protein-coding gene in the species Homo sapiens

N-Arachidonyl glycine receptor, also known as G protein-coupled receptor 18 (GPR18), is a protein that in humans is encoded by the GPR18 gene. Along with the other previously orphan receptors GPR55 and GPR119, GPR18 has been found to be a receptor for endogenous lipid neurotransmitters, several of which also bind to cannabinoid receptors. It has been found to be involved in the regulation of intraocular pressure.

<span class="mw-page-title-main">GPR32</span> Human biochemical receptor

G protein-coupled receptor 32, also known as GPR32 or the RvD1 receptor, is a human receptor (biochemistry) belonging to the rhodopsin-like subfamily of G protein-coupled receptors.

In cell biology, efferocytosis is the process by which apoptotic cells are removed by phagocytic cells. It can be regarded as the 'burying of dead cells'.

<span class="mw-page-title-main">Maresin</span> Chemical compound

Maresin 1 (MaR1 or 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid) is a macrophage-derived mediator of inflammation resolution coined from macrophage mediator in resolving inflammation. Maresin 1, and more recently defined maresins, are 12-lipoxygenase-derived metabolites of the omega-3 fatty acid, docosahexaenoic acid (DHA), that possess potent anti-inflammatory, pro-resolving, protective, and pro-healing properties similar to a variety of other members of the specialized proresolving mediators (SPM) class of polyunsaturated fatty acid (PUFA) metabolites. SPM are dihydroxy, trihydroxy, and epoxy-hydroxy metabolites of long chain PUFA made by certain dioxygenase enzymes viz., cyclooxygenases and lipoxygenases. In addition to the maresins, this class of mediators includes: the 15-lipoxygenase (i.e. ALOX15 and/or possibly ALOX15B)-derived lipoxin A4 and B4 metabolites of the omega 6 fatty acid, arachidonic acid; the cyclooxygenase 2-derived resolvin E series metabolites of the omega 3 fatty acid, eicosapentaenoic acid; certain 15-lipoxygenase-derived resolvin D series metabolites of DHA; certain other 15-lipoxygenase-derived protectin D1 and related metabolites of DHA; and the more recently defined and therefore less fully studied 15-lipoxygenase-derived resolvin Dn-3DPA metabolites of the omega-3 fatty acid n-3 docosapentaenoic acid (n-3 DPA or clupanodonic acid), the cyclooxygenase 2-derived resolvin T metabolites of this clupanodonic acid, and the 15-lipoxygenase-derived products of the N-acetylated fatty acid amide of the DHA metabolite, docosahexaenoyl ethanolamide.

Protectin D1 also known as neuroprotectin D1 and abbreviated most commonly as PD1 or NPD1 is a member of the class of specialized proresolving mediators. Like other members of this class of polyunsaturated fatty acid metabolites, it possesses strong anti-inflammatory, anti-apoptotic and neuroprotective activity. PD1 is an aliphatic acyclic alkene 22 carbons in length with two hydroxyl groups at the 10 and 17 carbon positions and one carboxylic acid group at the one carbon position.

<span class="mw-page-title-main">15-Hydroxyeicosatetraenoic acid</span> Chemical compound

15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(S)-HETE, and 15S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(S)-hydroperoxyeicosatetraenoic acid (15(S)-HpETE). This initial hydroperoxide product is extremely short-lived in cells: if not otherwise metabolized, it is rapidly reduced to 15(S)-HETE. Both of these metabolites, depending on the cell type which forms them, can be further metabolized to 15-oxo-eicosatetraenoic acid (15-oxo-ETE), 5(S),15(S)-dihydroxy-eicosatetraenoic acid (5(S),15(S)-diHETE), 5-oxo-15(S)-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE), a subset of specialized pro-resolving mediators viz., the lipoxins, a class of pro-inflammatory mediators, the eoxins, and other products that have less well-defined activities and functions. Thus, 15(S)-HETE and 15(S)-HpETE, in addition to having intrinsic biological activities, are key precursors to numerous biologically active derivatives.

<span class="mw-page-title-main">Epoxydocosapentaenoic acid</span> Group of chemical compounds

Epoxide docosapentaenoic acids are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases metabolize polyunsaturated fatty acids (PUFAs) by converting one of their double bonds to an epoxide. In the best known of these metabolic pathways, cellular CYP epoxygenases metabolize the 20-carbon straight-chain omega-6 fatty acid, arachidonic acid, to epoxyeicosatrienoic acids (EETs); another CYP epoxygenase pathway metabolizes the 20-carbon omega-3 fatty acid, eicosapentaenoic acid (EPA), to epoxyeicosatetraenoic acids (EEQs). CYP epoxygenases similarly convert various other PUFAs to epoxides. These epoxide metabolites have a variety of activities. However, essentially all of them are rapidly converted to their corresponding, but in general far less active, vicinal dihydroxy fatty acids by ubiquitous cellular soluble epoxide hydrolase. Consequently, these epoxides, including EDPs, operate as short-lived signaling agents that regulate the function of their parent or nearby cells. The particular feature of EDPs distinguishing them from EETs is that they derive from omega-3 fatty acids and are suggested to be responsible for some of the beneficial effects attributed to omega-3 fatty acids and omega-3-rich foods such as fish oil.

Cytochrome P450 omega hydroxylases, also termed cytochrome P450 ω-hydroxylases, CYP450 omega hydroxylases, CYP450 ω-hydroxylases, CYP omega hydroxylase, CYP ω-hydroxylases, fatty acid omega hydroxylases, cytochrome P450 monooxygenases, and fatty acid monooxygenases, are a set of cytochrome P450-containing enzymes that catalyze the addition of a hydroxyl residue to a fatty acid substrate. The CYP omega hydroxylases are often referred to as monoxygenases; however, the monooxygenases are CYP450 enzymes that add a hydroxyl group to a wide range of xenobiotic and naturally occurring endobiotic substrates, most of which are not fatty acids. The CYP450 omega hydroxylases are accordingly better viewed as a subset of monooxygenases that have the ability to hydroxylate fatty acids. While once regarded as functioning mainly in the catabolism of dietary fatty acids, the omega oxygenases are now considered critical in the production or break-down of fatty acid-derived mediators which are made by cells and act within their cells of origin as autocrine signaling agents or on nearby cells as paracrine signaling agents to regulate various functions such as blood pressure control and inflammation.

Poxytrins or dihydroxy-E,Z,E-polyunsaturated fatty acids (dihydroxy-E,Z,E-PUFAs) are PUFA metabolites that possess two hydroxyl residues and three in-series conjugated double bonds in an E,Z,E cis–trans configuration. Poxytrins, unlike isomers with three conjugated double bonds in a different geometry, have unique platelet-inhibiting properties. The critical E,Z,E configuration may be involved in controlling platelets, and could prove useful in treating human conditions and diseases that involve pathological platelet activation.

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