Specialized Pro-resolving Mediators

Novel Mechanisms for Supporting a Healthy Inflammatory Response

By: Caitlin Higgins

The following arti cle is not endorsed and/or supported by The American Academy of Anti -Aging Medicine. The purposes of this publicati on do not imply endorsement and/or support of any author, company or theme related to this arti cle.

WHAT ARE PRO - RESOLVING LIPID MEDIATORS?

Specialized pro-resolving mediators (SPMs) are produced in human blood, milk, and brain tissue from naturally-occurring omega-3 and omega-6 polyunsaturated fatty acids that help support the body’s innate immune response during the “resolution phase” of acute in ammation, clearance of pathogenic microbes, support a normal pain response and promote tissue regeneration. 1 Researchers have discovered that these SPMs include a superfamily of endogenous lipid-based chemical mediators known as resolvins, maresins, protectins, and lipoxins.  ese unique metabolites actively down-regulate the in ammatory response without compromising a healthy immune system response. 2

SPMs themselves do not block the initial phases of acute in ammation, which is a vital response to injury, infection, and illness, but rather have been shown in research to evoke novel anti-in ammatory and pro-resolving mechanisms that aid in the process of resolving acute in ammation, accelerating the return to homeostatic balance within the body. 3  is active resolution process controlled by SPMs is done so via targeting immune cells to stop actively responding to pro-in ammatory chemical mediators, thus limiting overall in ammation. More speci cally, SPMs promote resolution by binding to G-protein coupled receptors that can modify cellular behaviors such as mediating pro-in ammatory chemokine, cytokine, and adipokine regulation, microRNA transcription and translocation, and cell tra c. 4 At the site of in ammation, SPMs promote clearance of damaging byproducts, microbes, and debris by enhancing macrophage phagocytosis. 5

RESOLUTION FOR PAIN MANAGEMENT, TISSUE REPAIR, & INFLAMMATION

SPMs may help support a normal pain response caused by in ammation and injury. Evidence from research studies shows that SPM biosynthesis and concentrations are much lower in circulation among patients with chronic in ammatory conditions. 6 An RCT observing a population who su er from chronic headaches showed that increasing omega-3 fatty acid intake while reducing omega-6s raised serum SPM levels which signi cantly

attenuated headache pain through increasing production of antinociceptive mediators and improving the overall quality of life. 7 In an animal model of rheumatoid arthritis with signi cantly lower levels of resolvin D3 mediators (members of the SPM family), when mice were given resolvin mediators, they experienced signi cantly improved joint pain, sti ness, and in ammation due to lower levels of leukocytes and in ammatory eicosanoid in ltration. 8

In an in vitro animal model of peritonitis, upon administration of maresin lipid mediators, neutrophilic phagocytosis of E. coli and bacteria at the site of infection increased signi cantly, reducing the resolution interval by 10 hours. 9

Furthermore, in a clinical trial of obese women, those who supplemented with omega-3 fatty acids had statistically signi cantly higher concentrations of DHA-derived resolvins which activated speci c genetic pathways that are responsible for up-regulating antioxidant enzymes and lipid metabolism in those subjects. 10

WHY SPMS?

Unlike common anti-in ammatory drugs and medications, SPMs have favorable pro les and fortunately do not suppress immune system function as they are naturally-produced and involved in the biological process of in ammatory resolution. Direct supplementation may help in facilitating the body’s natural response to in ammatory challenges caused by aging, physical traumas, in ammatory-rich/ nutrient-poor diets, chronic stress, infections, and other insults. Research suggests that supplementation with proresolving mediators may also be bene cial for those who have single nucleotide polymorphisms (SNPs) for enzymes involved in SPM biosyntheses, such as the ALX/FPR2 SNPs, dysfunctioning SPM receptors, and in ammatory autoimmune conditions, as well as for those whose diets are low in omega-3 essential fatty acids (e.g., wild-caught fatty  sh,  axseed, walnuts). 11 A diet enriched in omega3s, coupled with high-quality, highly-concentrated supplemental SPMs, is shown to have favorable e ects in reducing overall in ammation. 12

REFERENCES

1. Chiang, N., & Serhan, C. N. (2017). Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors. Molecular

Aspects of Medicine, 58, 114–129. doi:10.1016/j.mam.2017.03.005 2. Colas, R. A., Shinohara, M., Dalli, J., Chiang, N., & Serhan, C. N. (2014).

Identi cation and signature pro les for pro-resolving and in ammatory lipid mediators in human tissue. Cell Physiology, 307(1), C39-C54. doi: https://doi. org/10.1152/ajpcell.00024.2014 3. Serhan, C. N. (2014). Pro-resolving mediators are leads for resolution physiology.

Nature, 510, 92-101. doi: https://doi.org/10.1038/nature13479 4. Cooray SN, Gobbetti T, Montero-Melendez T, et al. Ligand-speci c conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. Proc Natl Acad Sci U S A. 2013;110(45):18232–18237. doi:10.1073/pnas.1308253110 5. Serhan, C. N., Chiang, N., & Dalli, J. (2015).  e resolution code of acute in ammation: Novel pro-resolving lipid mediators in resolution. Seminars in

Immunology, 27(3), 200–215. doi:10.1016/j.smim.2015.03.004 6. Norris, P. C., Skulas-Ray, A C., Riley, I., Richter, C. K., Kris-Etherton, P. M.,

Jensen, G. L., … Maddipati, K. R. (2018). Identi cation of specialized proresolving mediator clusters from healthy adults after intravenous low-dose endotoxin and omega-3 supplementation: a methodological validation. Scienti c

Reports, 8, 18050. Retrieved from https://www.nature.com/articles/s41598- 018-36679-4 7. Ramsden, C. E., Faurot, K., Zamora, D., Suchindran, C., MacIntosh, B., Gaylord,

S., … Mann, D. (2013). Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: A randomized trial. Pain, 154(11), 2441–2451. doi: 10.1016/j.pain.2013.07.028 8. Arnardottir, H. H., Dalli, J., Norling, L. V., Colas, R. A., Perretti, M., & Serhan,

C. N. (2016). Resolvin D3 is dysregulated in arthritis and reduces arthritic in ammation.  e Journal of Immunology, 197(6), 2362-2368. doi: https://doi. org/10.4049/jimmunol.1502268 9. Dalli, J., Chiang, N., & Serhan, C. N. (2014). Identi cation of 14-series sul doconjugated mediators that promote resolution of infection and organ protection.

Proceedings of the National Academy of Sciences of the United States of

America, 111(44), E4753–E4761. doi:10.1073/pnas.1415006111 10. Polus, A., Zapala, B., Razny, U., Gielicz, A., Kiec-Wilk, B., Malczewska-Malec,

M., … Dembinska-Kiec, A. (2016). Omega-3 fatty acid supplementation in uences the whole blood transcriptome in women with obesity, associated with pro-resolving lipid mediator production. Biochim Biophys Acta, 1861(11), 1746- 1755. doi: 10.1016/j.bbalip.2016.08.005 11. Recchiuti, A., Mattoscio, D. & Isopi, E. (2019). Roles, actions, and therapeutic potential of specialized pro-resolving mediators for the treatment of in ammation in cystic  brosis. Frontiers in Pharmacology: In ammation Pharmacology, 10(252). doi: https://doi.org/10.3389/fphar.2019.00252 12. Norling, L. V., Ly, L., & Dalli, J. (2017). Resolving in ammation by using nutrition therapy: roles for specialized pro-resolving mediators. Current

Opinion in Clinical Nutrition and Metabolic Care, 20(2), 145–152. doi:10.1097/

MCO.0000000000000353

MODULES AVAILABLE LIVE & ONLINE

Learn more about Aesthetic Medicine, one of the fastest growing and most profitable sectors in healthcare, through our Aesthetics Fellowship: a program that combines audiovisual lectures with hands-on clinical tutorials, and allows participants to learn the multiple benefits and applications of Aesthetic Medicine.

COURSE CURRICULUM

• 3 Didactic Modules • 4 Hands-On Training Modules • Level 4 Certification