Resolvins are specialized pro-resolving mediators (SPMs) derived from

omega-3 fatty acid Omega−3 fatty acids, also called omega−3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond three atoms away from the terminal methyl group in their ...

s, primarily eicosapentaenoic acid (EPA) and

docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega−3 fatty acid that is an important component of the human brain, cerebral cortex, skin, and retina. It is given the fatty acid notation 22:6(''n''−3). It can be synthesized from alpha-linolenic acid or ...

(DHA), as well as from two isomers of docosapentaenoic acid (DPA), one omega-3 and one omega-6 fatty acid. As autacoids similar to

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

s acting on local tissues, resolvins are under preliminary research for their involvement in promoting restoration of normal cellular function following the

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

that occurs after tissue injury. Resolvins belong to a class of

polyunsaturated fatty acid In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsa ...

(PUFA)

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s termed specialized proresolving mediators (SPMs).

Biochemistry and production

Resolvins (Rvs) fall into several sub-classes based on the straight chain PUFA from which they are formed and derive their unique structure. The resolvins Ds (RvDs) are metabolites of the 22-carbon PUFA, DHA (i.e. 4''Z'',7''Z'',10''Z'',13''Z'',16''Z'',19''Z''-docosahexaenoic acid); the resolvins Es (RvEs) are metabolites of the 20-carbon PUFA, EPA (i.e. 5''Z'',8''Z'',11''Z'',14''Z'',17''Z''-eicosapentaenoic acid); the resolvins are metabolites of the DPA isomer, osbond acid (i.e. 4''Z'',7''Z'',10''Z'',13''Z'',16''Z''-docosapentaenoic acid); the resolvins are metabolites of the DPA isomer, clupanodonic acid (i.e. 7''Z'',10''Z'',13''Z'',16''Z'',19''Z''-docosapentaenoic acid); and the resolvins Ts (RvTs) are metabolites of clupanodonic acid, that possess a 17''R''

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

residue, whereas all resolvins have a 17''S'' hydroxyl residue. Certain isomers of RvDs are termed aspirin-triggered resolvin Ds (AT-RvDs) because their synthesis is initiated by a drug-modified COX-2 enzyme to form 17(''R'') hydroxyl rather than 17(''S'') hydroxyl residue of the RvEs; however, an unidentified as of 2023 cytochrome P450 enzyme(s) may also form this 17(''R'')-hydroxy intermediate and thereby contribute to the production of AT-RvEs. All of the cited resolvins except the are metabolites of omega-3 fatty acids. The following oxygenase enzymes may be responsible for metabolizing PUFA to resolvins: 15-lipoxygenase-1 (i.e.

ALOX15 ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically import ...

), possibly 15-lipoxygenase-2 (i.e.

ALOX15B Arachidonate 15-lipoxygenase type II is an enzyme that in humans is encoded by the ''ALOX15B'' gene. ALOX15B, also known as 15-lipoxygenase-2 (15-LO-2 or 15-LOX-2), is distinguished from its related oxygenase, ALOX15 or 15-lipoxygenase-1. Funct ...

), 5-lipoxygenase (i.e. ALOX5), cyclooxygenase-2 (i.e. COX-2), and certain

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

monooxygenase Monooxygenases are enzymes that incorporate one hydroxyl group (−OH) into substrates in many metabolic pathways. In this reaction, the two atoms of dioxygen are reduced to one hydroxyl group and one H2O molecule by the concomitant oxidation of ...

Resolvin Ds

RvDs are poly-hydroxyl metabolites of DHA. To date, six RvDs, which vary in the number, position, and

chirality Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable fro ...

of their hydroxyl residues as well as the position and

cis–trans isomerism ''Cis''–''trans'' isomerism, also known as geometric isomerism, describes certain arrangements of atoms within molecules. The prefixes "''cis''" and "''trans''" are from Latin: "this side of" and "the other side of", respectively. In the cont ...

of their 6

double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...

s, have been described. These are: RvD1 (7''S'',8''R'',17''S''-trihydroxy-DHA), RvD2 (7''S'',16''R'',17''S''-trihydroxy-DHA), RvD3 (4''S'',7''R'',17''S''-trihydroxy-DHA), RvD4 (4''S'',5,17''S''-trihydroxy-DHA; chirality at position 5 not yet determined as of 2023), RvD5 (7''S'',17''S''-dihydroxy-DHA), and RvD6 (4''S'',17''S''-dihydroxy-DHA). (The structures of these RvDs are further defined at ). These metabolites are formed by a wide range of cells and tissues by the initial metabolism of DHA to 7''S''-hydroperoxy-DHA and 4''S''-hydroperoxy-DHA by a 15-lipoxygenase (either ALOX15 or possibly ALOX15B) followed by the further metabolism of the two intermediates by ALOX5 to their 17-hydroperoxy derivatives; these di-hydroperoxy products are further altered to the cited RvDs by these oxygenases or by non-enzymatic reactions and the conversion of their peroxy residues ubiquitous cellular peroxidases.

Resolvin Es

RvEs are di- or tri-hydroxyl metabolites of EPA. To date, four RvEs have been described: RvE1 (5''S'',12''R'',18''R''-trihydroxy-EPA), 18''S''-Rv1 (5''S'',12''R'',18''S''-trihydroxy-EPA), RvE2 (5''S'',18''R''-dihydroxy-EPA), and RvE3 (17''R'',18''R/S''-dihydroxy-EPA). (Structures of the RvEs are further defined at ). Resolvins Es are formed in manner similar to AT resolvins Ts. COX-2 modified in activity by aspirin or atorvastatin or, alternatively, a microbial or possibly mammalian

monoxygenase metabolizes EPA to its 18''R''-hydroperoxy derivative; this intermediate is then further metabolized by ALOX5 to a 5,6 epoxide which is hydrolyzed enzymatically or non-enzymatically to RvE1 and 18''S''-RvE1 or reduced to RvE2; alternatively the 18''R''-hydroperoxide is converted to the 17''R'',18''S'' vicinal diol product, RvE3.

T series resolvins

Human

platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...

s pretreated with

aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...

atorvastatin Atorvastatin, sold under the brand name Lipitor among others, is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a ...

metabolize the omega-3 DPA, clupanodonic acid (DPA_n-3) by aspirin-treated or atorvastatin-treated COX-2 to a 13''S''-hydroperoxy intermediate (aspirin and atorvastatin change the activity of COX-2 from a cyclooxygenase to a hydroxyperoxidase-forming enzyme. The intermediate is then passed to nearby human

neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...

s which metabolize it, probably by ALOX5 enzyme activity, to four poly-

metabolites: RvT1 (7''S'',13''R'',20''S''-trihydroxy-8''E'',10''Z'',14''E'',16''Z'',18''E''-DPA), RvT2 (7''S'',12''R'',13''S''-trihydroxy-8''Z'',10''E'',14''E'',16''Z'',19''Z''-DPA), RvT3 (7''S'',8''R'',13''S''-trihydroxy-9''E'',11''E'',14''E'',16''Z'',19''Z''-DPA), and RvT4 (7''S'',13''R''-dihydroxy-8''E'',10''Z'',14''E'',16''Z'',19''Z''-DPA). Subsequent studies found that these four RvTs are also formed by mixtures of human neutrophils and vascular

endothelium The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...

cells and, additionally, are detected in the infected tissues of rodents and humans.

Putative mechanisms

Following tissue injury, the inflammatory response is a protective process to promote restoration of the tissue to

homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...

. Resolution of inflammation involves various specialized lipid mediators, including resolvins. Resolvins are under laboratory research for their potential to act through

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

s (GPRs): 1) RvD1 and AT-RvD1 act through the formyl peptide receptor 2, which is also activated by certain lipoxins and is therefore often termed the ALX/FPR2 receptor; 2) RvD1, AT-RVD1, RvD3, AT-RvD3, and RvD5 act through the GPR32 receptor which is now also termed the RVD1 receptor; 3) RvD2 acts through the GPR18 receptor also now termed the RvD2 receptor; and 4) RvE1 and the 18(''S'') analog of RvE1 are full activators while RvE2 is a partial activator of the CMKLR1 receptor. All of these receptors activate their parent cells through standard GPR-mobilized pathways. RvE1, 18(''S'')-RvE1, and RvE2 inhibit the leukotriene B4 receptor 1 which is the receptor for inflammation-promoting PUFA metabolites such as LTB4 and the ''R'' stereoisomer of 12-HETE; by inhibiting the action of these pro-inflammatory mediators.

References

{{reflist, 30em Lipids Eicosanoids Docosanoids