Resolvins are

specialized pro-resolving mediators 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 ...

(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 chem ...

s, primarily

eicosapentaenoic acid Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega-3 fatty acid. In physiological literature, it is given the name 20:5(n-3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid with a 20-c ...

(EPA) and

docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-lino ...

(DHA), as well as

docosapentaenoic acid Docosapentaenoic acid (DPA) designates any straight chain 22:5 fatty acid, that is a straight chain open chain type of polyunsaturated fatty acid (PUFA) which contains 22 carbons and 5 double bonds. DPA is primarily used to designate two isomers, ' ...

(DPA) and

clupanodonic acid Docosapentaenoic acid (DPA) designates any straight chain 22:5 fatty acid, that is a straight chain open chain type of polyunsaturated fatty acid (PUFA) which contains 22 carbons and 5 double bonds. DPA is primarily used to designate two isomers, ...

. As

autacoid Autacoids or "autocoids" are biological factors (molecules) which act like local hormones, have a brief duration, and act near their site of synthesis. The word ''autacoid'' comes from the Greek words "autos" (self) and "acos" (relief; i.e., drug) ...

s similar to

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

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 la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

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

polyunsaturated fatty acid Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...

(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 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 ...

(SPMs).

Biochemistry and production

Resolvins (Rvs) fall into several sub-classes based on the straight chain PUFA from which they are formed and/or a unique aspect of their structure. The Resolvin 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 resolvin Es (RvEs) are metabolites of the 20-carbon PUFA, EPA (i.e. 5''Z'',8''Z'',11''Z'',14''Z'',17''Z''-5,8,11,14,17-eicosapentaenoic acid); the resolvin D_n-6DPA (RvDs_n-6DPA) are metabolites of the DPA isomer, osbond acid (i.e. 4''Z'',7''Z'',10''Z'',13''Z'',16''Z''-docosapentaenoic acid); the resolvin D_n-3DPA (RvD_n-3DPA) are metabolites of the DPA isomer, clupanodonic acid (i.e. 7''Z'',10''Z'',13''Z'',16''Z'',19''Z'')-docosapentaenoic acid); and the resolvin Ts (RvTs) are metabolites of clupanodonic acid that, in contrast to (RvDs_n-3DPA (all of which possess a 17''S''-

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), possess a 17''R''-hydroxyl residue. Certain isomers of RvDs are termed aspirin-triggered resolvin Ds (AT-RvDs) because their synthesis is initiated by a drug-modified

COX2 Cytochrome c oxidase subunit 2, also known as cytochrome c oxidase polypeptide II, is a protein that in humans is encoded by the MT-CO2 gene. Cytochrome c oxidase subunit II, abbreviated COXII, COX2, COII, or MT-CO2, is the second subunit of c ...

enzyme to form 17(''R'')-hydroxyl rather than 17(''S'')-hydroxyl residue of the ReVEs; however, an as yet unidentified cytochrome P450 enzyme(s) may also forms this 17(''R'')-hydroxy intermediate and thereby contribute to the production of AT-RvEs. All of the cited resolvins except the RvDs_n-6DPAs are metabolites of

omega-3 fatty acids 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 chem ...

. The following

oxygenase An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 (as in air) to it. The oxygenases form a class of oxidoreductases; their EC number is EC 1.13 or EC 1.14. Discoverers Oxygenases were disco ...

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 importa ...

), 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 Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme (EC 1.13.11.34) that in humans is encoded by the ''ALOX5'' gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase fa ...

), cyclooxygenase-2 (i.e.

COX-2 Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene. ...

), and certain

Cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

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 o ...

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 from ...

of their hydroxyl residues as well as the position and cis-trans isomerism of their 6

double bonds 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 betwee ...

, 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), RvD5 (7''S'',17''S''-dihydroxy-DHA), and RvD6 (4''S'',17''S''-dihydroxy-DHA). (The structures of these RvDs are further defined at Specialized proresolving mediators#DHA-derived Resolvins). 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 Specialized proresolving mediators#EPA-derived Resolvins.) Resolvin Es are formed in manner similar to AT resolving Ts. COX-2 modified in activity by aspirin or atorvastatin or, alternatively, a microbial or possibly mammalian

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

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 A diol is a chemical compound containing two hydroxyl groups ( groups). An aliphatic diol is also called a glycol. This pairing of functional groups is pervasive, and many subcategories have been identified. The most common industrial diol is e ...

product, RvE3.

T series resolvins

Human

platelets Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...

pretreated with

aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...

atorvastatin Atorvastatin 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 first-line treatment. It is taken by mouth. Common ...

metabolize the omega-3 DPA, clupanodonic acid (DPA_n-3) by aspirin-treated or atorvastatin-treated

to a 13''S''-hydroperoxy intermediate (aspirin and atorvastatin change the activity of COX2 from a cyclooxygenase to an hydroxyperoxidase-forming enzyme. The intermediate is then passed to nearby human

neutrophils Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

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

metabolites: RvT1 (7,13''R'',20-trihydroxy-DPA_n-3); RvT2 (7,8,13''R''-trihydroxy-DPA_n-3); RvT3 (7,12,13''R''-trihydroxy-8''Z'',10''E'',14''E'',16''Z'',19''Z''-DPA_n-3) and RvT4 (7,13''R''-dihydroxy-DPA_n-3). Subsequent studies found that these four RvTs are also formed by mixtures of human neutrophils and vascular endothelium 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) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...

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

G protein-coupled receptors 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 p ...

(GPRs): 1) RvD1 and AT-RvD1 act through the

Formyl peptide receptor 2 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 b ...

, 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 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. Gene The ''GPR32'' was initially identified and defined by mo ...

receptor which is now also termed the RVD1 receptor; 3) RvD2 acts through the

GPR18 ''N''-Arachidonyl glycine receptor (NAGly 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 ...

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 Chemokine like receptor 1 also known as ChemR23 (Chemerin Receptor 23) is a protein that in humans is encoded by the ''CMKLR1'' gene. Chemokine receptor-like 1 is a G protein-coupled receptor for the chemoattractant adipokine chemerin and the ome ...

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 Leukotriene B4 receptor 1 is a protein that in humans is encoded by the ''LTB4R'' gene. See also * Eicosanoid receptor Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that bind and respond to ...

which is the receptor for inflammation-promoting PUFA metabolites such as

LTB4 Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It has been shown to promote insulin resistance in obese mice. Biochemistry Leukotriene B4 (LTB4) is a leukotriene involved in inflammation. It is produced from leukocytes in respon ...

and the ''R'' stereoisomer of 12-HETE; by inhibiting the action of these pro-inflammatory mediators.

Preliminary research

Resolvin metabolites of EPA, DHA, and DPA and the

maresin Maresin 1 (MaR1 or 7''R'',14''S''-dihydroxy-4''Z'',8''E'',10''E'',12''Z'',16''Z'',19''Z''-docosahexaenoic acid) is a macrophage-derived mediator of inflammation resolution coined from macrophage mediator in resolving inflammation. Maresin 1, an ...

and

protectin D1 Protectin D1 also known as neuroprotectin D1 (when it acts in the nervous system) 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 fa ...

metabolites of DHA are under

basic research Basic research, also called pure research or fundamental research, is a type of scientific research with the aim of improving scientific theories for better understanding and prediction of natural or other phenomena. In contrast, applied resear ...

for their potential influences on inflammation. One human study reported no increase in urine or plasma resolvin content after consumption of fish oil compared to a non-omega-3 oil, either before or after challenge with

bacterial Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...

lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...

known to induce an inflammatory reaction. Preliminary studies in people with

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

kidney disease Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can ...

cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...

while receiving dietary PUFA or fish oil supplements indicated improvement of inflammation

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

s, possibly resulting from resolvins.

References

{{reflist, 30em Lipids Eicosanoids Docosanoids