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Resolvin D2 (RvD2)


Resolvins are metabolic byproducts of omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as the lesser-studied (to date) docosapentaenoic acid (DPA). Resolvins can be considered as autocoid-like in nature, in that they are similar to hormones, brief in their duration, and act at the site of their biochemical synthesis. Resolvins are under research for their involvement in promoting restoration of normal cellular function following acute inflammation that occurs after tissue injury.[1][2] Resolvins belong to a class of polyunsaturated fatty acid (PUFA) metabolites termed specialized proresolving mediators (SPMs).[3][4]

History of ω-3 PUFA's

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Over the past few decades, there have been many published reports on the benefits of dietary supplementation with omega-3 polyunsaturated fatty acids, through increased intake of linseed, canola, and most importantly fish oil(s)[5]. These reports have suggested that omega-3 PUFA's can have anti-inflammatory and immunoregulatory effects in a large number of diseases, where the common pathology is chronic, uncontrolled inflammation. More specifically, the potential for preventative or curative action in disease was demonstrated in a cardiovascular context such as asthma[6], as well as an anti-metastatic effect in colon cancer[7]. In a major animal study, the two major dietary ω-3's, EPA and DHA, were found to have a profound effect in protecting against sudden cardiac death in dog model[8]. More specifically, upon intravenous infusion of both the above-mentioned PUFA's, the dogs used in this study were prevented from suffering fatal ventricular arrhythmias. Furthermore, the emergence of these possibilities in the treatment of disease lead to large scale dietary studies in humans, the goal of which was to determine an effective recommended dietary intake[9]. The results of this study, performed with >11,000 patients suffering from cardiovascular disease, showed that taking ~1 g of ω-3 PUFA daily could protect against life-threatening myocardial infarction. Despite the vast amount of work in this field, the actual molecular mechanism(s) of how omega-3 PUFA's are exerting protective actions was largely understudied and undiscovered until the start of the 2000s.

Resolvins and the Inflammatory Response

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The role of the inflammatory process in human health has long been recognized, for the simple fact that every day our body is fighting off bacteria and microbes, healing tissue injuries, and maintaining a level of homeostasis. These inflammatory and immune responses go largely unnoticed however, and it was not until earlier this decade that the mechanism by which this process is self-limited and resolves was fully understood[10]. Rather than the resolution of inflammation being characterized as a passive process, it is now widely accepted as being biosynthetically active. The process is controlled and driven by biochemical mediators derived enzymatically from PUFAs (such as DHA), broadly known as specialized pro-resolving mediators. More specifically, a major family of SPMs are known as Resolvins, first coined by Charles Serhan and colleagues in 2002[11], have been shown to have a wide range of effects in regulating the inflammatory response and enhancing what is described as a "proresolution status"[11]. More specifically, Resolvins have been shown to have picogram to nanogram physiologic concentration, and are able to act in counter-regulating proinflammatory species (such as cytokines and chemokines). Additionally, these metabolic products are able to promote macrophage phagocytosis of cellular debris, clearance of apoptotic PMN, and killing of pathogens and other harmful microbes[12]. Interestingly enough, different Resolvins have been found to be both spatially and temporally regulated with regards to fighting off infection, responding to minor and severe tissue injuries, and reigning in the inflammatory response as a whole. RvD1 and RvD5 both have the ability to reduce bacterial titers in blood, through increasing macrophage and neutrophil phagocytosis[12]. RvD2 exerts a similar enhancement of phagocytic capabilities, in conditions of E. Coli and Staphylococcus aureus infections, and also has the ability to regulate T-cell differentiation that normally release inflammatory cytokines[12]. Furthermore, RvD3 can minimize lung inflammation induced by acid injury, and promote a rapid return to homeostasis[12].

Time-course of the acute inflammatory response, beginning with formation of edema and PMN infiltration, and ending with phagocytic cell-type recruitment that biosynthetically produce Resolvins and other SPMs. The cessation of this process yields complete resolution of inflammation, and takes place over the course of hours to days.

Biochemistry and production

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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 D-series and E-series Resolvins are the most heavily studied, with the subsequent categories below those not under as heavy research.

  • The Resolvin Ds (RvDs) are metabolites of the 22-carbon PUFA, DHA (i.e. 4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoic acid)
  • The Resolvin Es (RvEs) are metabolites of the 20-carbon PUFA, EPA (i.e. 5Z,8Z,11Z,14Z,17Z-5,8,11,14,17-eicosapentaenoic acid)
  • Resolvin Dn-6DPA (RvDsn-6DPA) are metabolites of the DPA isomer, osbond acid (i.e. 4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid)
  • Resolvin Dn-3DPA (RvDn-3DPA) are metabolites of the DPA isomer, clupanodonic acid (i.e. 7Z,10Z,13Z,16Z,19Z)-docosapentaenoic acid)
  • Resolvin T's (RvTs) are metabolites of clupanodonic acid that, in contrast to (RvDsn-3DPA (all of which possess a 17S-hydroxyl residue), possess a 17R-hydroxyl residue.

Certain isomers of RvDs are termed aspirin-triggered resolvins (AT-RvDs) because their synthesis is initiated by a drug-modified COX2 enzyme to form 17(R)-hydroxyl rather than 17(S)-hydroxyl residue of the RvEs; however, an unidentified 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 RvDsn-6DPAs are metabolites of omega-3 fatty acids.[3][4]

Enzymatic Synthesis

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The following oxygenase enzymes are responsible for metabolizing PUFA to resolvins: 15-lipoxygenase-1 (i.e. ALOX15), possibly 15-lipoxygenase-2 (i.e. ALOX15B), 5-lipoxygenase (i.e. ALOX5), cyclooxygenase-2 (i.e. COX-2), and certain Cytochrome P450 monooxygenases.[3][13]

In the image seen below, the SPM network is detailed, illustrating the enzymes, intermediates, and precursors of the SPM superfamily’s biosynthesis from omega-3 PUFA (DHA, EPA, and DPA). [14].

SPM schematic

Receptor Binding

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Resolvins have been found to act distinctly through G-protein couple receptors (GPCRs), with some of the Resolvins having to ability to bind to multiple different receptors[4][15].

  • RvD1 and AT-RvD1 are able act through the Formyl peptide receptor 2
  • RvD1, AT-RVD1, RvD3, AT-RvD3, and RvD5 act through the GPR32 receptor which has also been described as the RVD1 receptor.
  • RvD2 acts through the GPR18 receptor, and is described as an "orphan" receptor.
  • RvE1 and the 18(S) analog of RvE1 are full activators while RvE2 is a partial activator of the CMKLR1receptor.
Generic G-protein coupled receptor, depicting the binding of a hormone and the subsequent conformational changes and signaling cascade that occurs upon ligand stimulation.


Resolvins in Animal Models

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Below are selected examples of the actions of Resolvins in preclinical animal disease systems:

  • RvE1: regulates neutrophil phagocytosis in a mouse model of Type 2 Diabetes[16].
  • RvD1: decreases macrophage accumulation in adipose tissue and improves insulin sensitivity in obese-diabetic mice[17]
  • RvD2: anti-cancer and analgesic effects in a mouse xenograft model of oral squamous cell carcinoma[18]
  • RvD3: host protective and aids in antimicrobial defense in a E.coli peritonitis mouse model[19]

Recent insights in the treatment of human disease

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Resolvins were first identified in the inflammatory exudates of mice in vivo experiments, and in the past decade the translational impact to humans has been under intense research[5]. Numerous examples of human studies looking at identification of Resolvins, or more broadly the precursor omega-3 fatty acids, in human disease states, have begun to take hold in the field of inflammation research. An important finding in this field that helped spur this movement stemmed from the work of Dr. Charles Serhan and colleagues, whereby they were able to identify Resolvins and numerous other specialized pro-resolving mediators in human tissues[20]. A bulleted list, along with the major findings of each respective study, can be seen below:

  • ω-3 supplementation, and further metabolizing to Resolvins, results in reduced pain score and reduced inflammation in synovial fluid in in humans undergoing treatment for arthritis[21].
  • ω-3 supplementation (branded as 'Lovaza') given to coronary artery disease patients results in reduced inflammation and reduction of clots, as compared to study patients that were not receiving Lovaza[22].
  • Resolvin D1-D4 were identified in human breast milk and help to protect against inflammatory mastitis[23].
  • Resolvin D1 was found to be reduced in CSF and hippocampus of Alzheimer's disease patients, suggestion therapeutic intervention could potentially aid in treatment of the disease, or disease-associated inflammation[24].
  • Resolvin D1 and D2 were found to be increased in human tuberculosis disease patients (as compared to healthy patients), and can serve as biomarkers or provide insight into disease pathogenesis, which could then lead to development of treatment strategies[25].
  • Resolvin D1 and D2 were identified in human sepsis patients, and correlated positively with reduced inflammation and patient survival, thus providing a biomarker for improved survival outcomes[26].
  • Randomized clinical trial on the impact of ω-3 supplementation results in reduced inflammation in chronic kidney disease, as well as an increase in Resolvin D1[27].
  • Topical application of ω-3 FA's results in reduced inflammation in patients with dry-eye disease[28].

References

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  1. ^ Moro, K; Nagahashi, M; Ramanathan, R; Takabe, K; Wakai, T (2016). "Resolvins and omega three polyunsaturated fatty acids: Clinical implications in inflammatory diseases and cancer". World Journal of Clinical Cases. 4 (7): 155–164. doi:10.12998/wjcc.v4.i7.155. PMC 4945585. PMID 27458590.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  2. ^ Balta, M. G; Loos, B. G; Nicu, E. A (2017). "Emerging Concepts in the Resolution of Periodontal Inflammation: A Role for Resolvin E1". Frontiers in Immunology. 8: 1682. doi:10.3389/fimmu.2017.01682. PMC 5735081. PMID 29312286.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ a b c Serhan, C. N.; Chiang, N; Dalli, J; Levy, B. D. (2014). "Lipid mediators in the resolution of inflammation". Cold Spring Harbor Perspectives in Biology. 7 (2): a016311. doi:10.1101/cshperspect.a016311. PMC 4315926. PMID 25359497.
  4. ^ a b c Duvall, M. G.; Levy, B. D. (2015). "DHA- and EPA-derived resolvins, protectins, and maresins in airway inflammation". European Journal of Pharmacology. 785: 144–55. doi:10.1016/j.ejphar.2015.11.001. PMC 4854800. PMID 26546247.
  5. ^ a b Serhan, Charles N.; Clish, Clary B.; Brannon, Jessica; Colgan, Sean P.; Chiang, Nan; Gronert, Karsten (2000-10-16). "Novel Functional Sets of Lipid-Derived Mediators with Antiinflammatory Actions Generated from Omega-3 Fatty Acids via Cyclooxygenase 2–Nonsteroidal Antiinflammatory Drugs and Transcellular Processing". The Journal of Experimental Medicine. 192 (8): 1197–1204. doi:10.1084/jem.192.8.1197. ISSN 0022-1007. PMC 2195872. PMID 11034610.
  6. ^ Breslow, Jan L. (06 2006). "n-3 fatty acids and cardiovascular disease". The American Journal of Clinical Nutrition. 83 (6 Suppl): 1477S–1482S. doi:10.1093/ajcn/83.6.1477S. ISSN 0002-9165. PMID 16841857. {{cite journal}}: Check date values in: |date= (help)
  7. ^ Iigo, M.; Nakagawa, T.; Ishikawa, C.; Iwahori, Y.; Asamoto, M.; Yazawa, K.; Araki, E.; Tsuda, H. (1997). "Inhibitory effects of docosahexaenoic acid on colon carcinoma 26 metastasis to the lung". British Journal of Cancer. 75 (5): 650–655. doi:10.1038/bjc.1997.116. ISSN 0007-0920. PMC 2063338. PMID 9043019.
  8. ^ Billman, G. E.; Kang, J. X.; Leaf, A. (1999-05-11). "Prevention of sudden cardiac death by dietary pure omega-3 polyunsaturated fatty acids in dogs". Circulation. 99 (18): 2452–2457. doi:10.1161/01.cir.99.18.2452. ISSN 1524-4539. PMID 10318669.
  9. ^ "Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico". Lancet (London, England). 354 (9177): 447–455. 1999-08-07. doi:10.1016/S0140-6736(99)07072-5. ISSN 0140-6736. PMID 10465168. S2CID 2649173.
  10. ^ Serhan, Charles N.; Petasis, Nicos A. (2011-10-12). "Resolvins and Protectins in Inflammation-Resolution". Chemical Reviews. 111 (10): 5922–5943. doi:10.1021/cr100396c. ISSN 0009-2665. PMC 3192290. PMID 21766791.
  11. ^ a b Serhan, Charles N.; Hong, Song; Gronert, Karsten; Colgan, Sean P.; Devchand, Pallavi R.; Mirick, Gudrun; Moussignac, Rose-Laure (2002-10-21). "Resolvins". The Journal of Experimental Medicine. 196 (8): 1025–1037. doi:10.1084/jem.20020760. ISSN 0022-1007. PMC 2194036. PMID 12391014.
  12. ^ a b c d Serhan, Charles N.; Levy, Bruce D. (07 02, 2018). "Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators". The Journal of Clinical Investigation. 128 (7): 2657–2669. doi:10.1172/JCI97943. ISSN 1558-8238. PMC 6025982. PMID 29757195. {{cite journal}}: Check date values in: |date= (help)
  13. ^ Qu Q, Xuan W, Fan GH (2015). "Roles of resolvins in the resolution of acute inflammation". Cell Biology International. 39 (1): 3–22. doi:10.1002/cbin.10345. PMID 25052386. S2CID 10160642.
  14. ^ Serhan, Charles N.; Levy, Bruce D. (2018-05-14). "Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators". Journal of Clinical Investigation. 128 (7): 2657–2669. doi:10.1172/jci97943. ISSN 0021-9738. PMC 6025982. PMID 29757195.
  15. ^ Serhan, Charles N. (2014-06-05). "Novel Pro-Resolving Lipid Mediators in Inflammation Are Leads for Resolution Physiology". Nature. 510 (7503): 92–101. doi:10.1038/nature13479. ISSN 0028-0836. PMC 4263681. PMID 24899309.
  16. ^ Herrera, Bruno S.; Hasturk, Hatice; Kantarci, Alpdogan; Freire, Marcelo O.; Nguyen, Olivia; Kansal, Shevali; Van Dyke, Thomas E. (2015-2). "Impact of Resolvin E1 on Murine Neutrophil Phagocytosis in Type 2 Diabetes". Infection and Immunity. 83 (2): 792–801. doi:10.1128/IAI.02444-14. ISSN 0019-9567. PMC 4294250. PMID 25486994. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Hellmann, Jason; Tang, Yunan; Kosuri, Madhavi; Bhatnagar, Aruni; Spite, Matthew (2011-7). "Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese-diabetic mice". The FASEB Journal. 25 (7): 2399–2407. doi:10.1096/fj.10-178657. ISSN 0892-6638. PMC 3114534. PMID 21478260. {{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)
  18. ^ Ye, Yi; Scheff, Nicole N.; Bernabé, Daniel; Salvo, Elizabeth; Ono, Kentaro; Liu, Cheng; Veeramachaneni, Ratna; Viet, Chi T.; Viet, Dan T. (2018-09-01). "Anti-cancer and analgesic effects of resolvin D2 in oral squamous cell carcinoma". Neuropharmacology. 139: 182–193. doi:10.1016/j.neuropharm.2018.07.016. ISSN 1873-7064. PMID 30009833. S2CID 51629080.
  19. ^ Norris, Paul C.; Arnardottir, Hildur; Sanger, Julia M.; Fichtner, David; Keyes, Gregory S.; Serhan, Charles N. (2018-11). "Resolvin D3 multi-level proresolving actions are host protective during infection". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 138: 81–89. doi:10.1016/j.plefa.2016.01.001. ISSN 1532-2823. PMC 4958045. PMID 26858146. {{cite journal}}: Check date values in: |date= (help)
  20. ^ Colas, Romain A.; Shinohara, Masakazu; Dalli, Jesmond; Chiang, Nan; Serhan, Charles N. (2014-07-01). "Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue". American Journal of Physiology. Cell Physiology. 307 (1): C39–54. doi:10.1152/ajpcell.00024.2014. ISSN 1522-1563. PMC 4080182. PMID 24696140.
  21. ^ Barden, Anne E.; Moghaddami, Mahin; Mas, Emilie; Phillips, Michael; Cleland, Leslie G.; Mori, Trevor A. (2016-4). "Specialised pro-resolving mediators of inflammation in inflammatory arthritis". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 107: 24–29. doi:10.1016/j.plefa.2016.03.004. ISSN 1532-2823. PMID 27033423. {{cite journal}}: Check date values in: |date= (help)
  22. ^ Elajami, Tarec K.; Colas, Romain A.; Dalli, Jesmond; Chiang, Nan; Serhan, Charles N.; Welty, Francine K. (08 2016). "Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling". FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 30 (8): 2792–2801. doi:10.1096/fj.201500155R. ISSN 1530-6860. PMC 4970606. PMID 27121596. {{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)
  23. ^ Arnardottir, Hildur; Orr, Sarah K.; Dalli, Jesmond; Serhan, Charles N. (05 2016). "Human milk proresolving mediators stimulate resolution of acute inflammation". Mucosal Immunology. 9 (3): 757–766. doi:10.1038/mi.2015.99. ISSN 1935-3456. PMC 4833718. PMID 26462421. {{cite journal}}: Check date values in: |date= (help)
  24. ^ Wang, Xiuzhe; Zhu, Mingqin; Hjorth, Erik; Cortés-Toro, Veronica; Eyjolfsdottir, Helga; Graff, Caroline; Nennesmo, Inger; Palmblad, Jan; Eriksdotter, Maria (2015-1). "Resolution of inflammation is altered in Alzheimer's disease". Alzheimer's & Dementia : The Journal of the Alzheimer's Association. 11 (1): 40–50.e2. doi:10.1016/j.jalz.2013.12.024. ISSN 1552-5260. PMC 4275415. PMID 24530025. {{cite journal}}: Check date values in: |date= (help)
  25. ^ Frediani, Jennifer K.; Jones, Dean P.; Tukvadze, Nestan; Uppal, Karan; Sanikidze, Eka; Kipiani, Maia; Tran, ViLinh T.; Hebbar, Gautam; Walker, Douglas I. (2014-10-15). "Plasma Metabolomics in Human Pulmonary Tuberculosis Disease: A Pilot Study". PLOS ONE. 9 (10): e108854. doi:10.1371/journal.pone.0108854. ISSN 1932-6203. PMC 4198093. PMID 25329995.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  26. ^ Dalli, Jesmond; Colas, Romain A.; Quintana, Carolina; Barragan-Bradford, Diana; Hurwitz, Shelley; Levy, Bruce D.; Choi, Augustine M.; Serhan, Charles N.; Baron, Rebecca M. (2017-1). "Human Sepsis Eicosanoid and Proresolving Lipid Mediator Temporal Profiles: Correlations With Survival and Clinical Outcomes". Critical Care Medicine. 45 (1): 58–68. doi:10.1097/CCM.0000000000002014. ISSN 1530-0293. PMC 5549882. PMID 27632672. {{cite journal}}: Check date values in: |date= (help)
  27. ^ Mas, Emilie; Barden, Anne; Burke, Valerie; Beilin, Lawrence J.; Watts, Gerald F.; Huang, Rae-Chi; Puddey, Ian B.; Irish, Ashley B.; Mori, Trevor A. (2016-4). "A randomized controlled trial of the effects of n-3 fatty acids on resolvins in chronic kidney disease". Clinical Nutrition (Edinburgh, Scotland). 35 (2): 331–336. doi:10.1016/j.clnu.2015.04.004. ISSN 1532-1983. PMID 25908532. {{cite journal}}: Check date values in: |date= (help)
  28. ^ Barabino, Stefano; Horwath-Winter, Jutta; Messmer, Elisabeth M.; Rolando, Maurizio; Aragona, Pasquale; Kinoshita, Shigeru (2017-11). "The role of systemic and topical fatty acids for dry eye treatment". Progress in Retinal and Eye Research. 61: 23–34. doi:10.1016/j.preteyeres.2017.05.003. ISSN 1873-1635. PMID 28532687. S2CID 39901578. {{cite journal}}: Check date values in: |date= (help)
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