During the past decade, a great deal of research has identified a class of lipid signaling chemicals, identified in circulation and tissues throughout the body,1,2 referred to as resolving mediators. These omega-3 derived molecules actively coordinate the resolution of inflammation and promote the tissue repair process.1-3
Unfortunately, some individuals express insufficient levels of endogenous
specialized pro-resolving mediators—thought to be related to lifestyle
behaviors, dietary choices, age, or negative health conditions—in
response to an inflammatory challenge.1-3 As a result, the body’s inflammation resolution
activities can be blunted, leading to unresolved, chronic
The Body Converts EPA, DPA and DHA to Resolving Mediators
Resolving mediators are produced naturally in the body
from unsaturated fatty acids—predominantly omega-3 EPA and DHA (Figure 1).2-4 Although EPA and DHA are the precursors of specialized pro-resolving mediators, they do not have direct pro-resolving properties.1,2,4 They
require multiple downstream enzymatic conversions to form 17-HDHA and 18-HEPE resolving mediators, which are further converted into specialized pro-resolving mediators that directly communicate with immune cells (e.g. resolvins, meresins, and protectins). Supplementing the diet with 14-HDHA, 17-HDHA, and 18-HEPE resolving mediators may be an effective approach for certain individuals to increasing circulating levels of specialized pro-resolving mediators in the body as well as by increasing consumption of
omega-3 fatty acids.
Resolving Mediators and Inflammation
- Inflammation is triggered by tissue damage or infection.
- In this phase, the immune system produces inflammatory chemicals and immune components such as white blood cells migrate to the damaged area to remove debris.
- After the inflammatory process has run its course, cells release EPA, DPA, and DHA fatty acids which are transformed into intermediate substances referred to as resolving mediators (14-HDHA, 17-HDHA, 18-HEPE). Resolving mediators convert into the required specialized resolving mediators (resolvins, protectins, etc.) at the site of the injury.
- Specialized pro resolving mediators then communicate with immune cells calming inflammation and initiating the repair phase.
Inflammation Initiation and Resolution is a “Phased” Process
Each phase of the inflammatory response is linked, and therefore the initiation phase
is required for the resolution phase to occur.5,6 Interestingly, the use of
certain traditional anti-inflammatory therapies such as NSAIDs are
considered “resolution disrupters.”1 They block the initiation phase activities
by inhibiting the synthesis of eicosanoids involved in inflammation
initiation, thereby impacting the subsequent production of specialized
pro-resolving mediators needed for inflammation resolution (Figure 1).1
Resolving Mediators are the Orchestrators of the Inflammation Resolution Phase
Until recently, scientists believed that after an inflammatory response was initiated in response to damage or infection, pro-inflammatory signals dissipated over time and inflammation faded away without assistance leading to an eventual return to homeostasis or balance.2 To the contrary, it has become clear, as stated above, that inflammatory activity has an initiation phase and a resolution phase, and resolution of inflammation is an active and controlled process.2-4 Without effective resolution, a return to homeostasis will not occur. Specialized pro-resolving mediators, including resolvins (Rvs), protectins (PDs), and maresins (Mars), are the orchestrators driving this active resolution process:2-4
- Limiting excessive white blood cell infiltration in damaged tissues
- Stimulating macrophage breakdown of cellular debris
- Decreasing pro-inflammatory signaling
- Promoting tissue regeneration and restoring immune homeostasis
Preliminary evidence from various experiments supports the role resolving and specialized pro-resolving mediators may be having in resolving inflammation. The research indicates, nutritional strategies that enhance production of specialized pro-resolving mediators may be beneficial in the management of health conditions associated with chronic unresolved inflammation. The following are areas that appear most promising.
Joints and Arthritis
OA is characterized by an increase in inflammatory cells and biomarkers in affected joints.8
- In patients with arthritis, lower levels of Rvs, 17-HDHA, and 18-HEPE were correlated with higher inflammatory markers and pain scores.9
- In animal models, treatment with resolvins reduced joint inflammation,
reduced arthritis symptoms and severity, and stimulated
- Neuroinflammation is associated with cognitive decline.13,14
Lower levels of specific neuroprotectin and resolvins in the brain and cerebrospinal fluid has been noted in Alzheimer’s disease and other forms of dementia.15,16
- Levels of lipoxins and resolvins measured in brain tissues from AD patients, were positively correlated with cognitive function as determined by various testing scores.17
Blood Sugar Regulation and Obesity
Fat tissue can contribute to an increase in chronic uncontrolled inflammation, which can result in adverse metabolic outcomes such as insulin resistance and obesity.18
- In adipose tissues of humans with metabolic syndrome and obese mice, levels of resolvins, 17-HDHA, or 18-HEPE were reduced.18
- Fat cells treatment with resolvins are able to promote inflammation resolution activities, and reduced pro-inflammatory
signaling agents, potentially transforming adipose tissue function.2,18
- In overweight individuals with metabolic syndrome, the appearance of 17-HDHA and 18-HEPE was reduced following fish oil supplementation, high body fat levels can impede the biosynthesis of specialized pro-resolving mediators.19
Inflammatory Bowel Disorders
Crohn’s disease and ulcerative colitis lead to long-term and occasionally irreversible impairment of gastrointestinal structure and function.20
- In animal models, resolvins, maresins, and 17-HDHA have been shown to help reduce tissue damage, reduce inflammation and immune cell infiltration, maintain body weight, and increase survival.21-24
Sources of Resolving and Specialized Resolving Mediators
Various fractionated (super critical extraction) fish oil products are available that are high in resolving mediators which are likely converted into active Specialized Pro Resolving Mediators in the body. These products mainly feature the 14-HDHA, 17-HDHA, and 18-HEPE oxylipids.
Various multi-nutrient, minimally refined marine lipids from Alaskan cod and salmon, offer high levels of the resolving mediators (14-HDHA, 17-HDHA, and 18-EPE), as well as a wide range of active Specialized Pro Resolving Mediators albeit at trace levels.Let the Healing Begin! Shop for Steward Cod Liver Oil
- Serhan, CN, Nature, 2014. 510(7503): p. 92-101.
- Spite, M, et al., Cell Metab, 2014. 19(1): p. 21-36.
- Recchiuti, A, J Gerontol Geriat Res, 2014. 3:151.
- Serhan, CN, et al., Curr Opin Pharmacol, 2013. 13(4): p. 632-40.
- Serhan, CN, et al., Faseb J, 2007. 21(2): p. 325-32.
- Serhan, CN, et al., Nat Immunol, 2005. 6(12): p. 1191-7.
- Nathan, C, et al., Cell, 2010. 140(6): p. 871-82.
- Sellam, J, et al., Nat Rev Rheumatol, 2010. 6(11): p. 625-35.
- Barden, AE, et al., Prostaglandins Leukot Essent Fatty Acids, 2016. 107: p. 24-9.
- Norling, LV, et al., JCI Insight, 2016. 1(5): p. e85922.
- Lima-Garcia, JF, et al., Br J Pharmacol, 2011. 164(2): p. 278-93.
- Arnardottir, HH, et al., J Immunol, 2016. 197(6): p. 2362-8.
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- Yaffe, K, et al., Neurology, 2003. 61(1): p. 76-80.
- Lukiw, WJ, et al., J Clin Invest, 2005. 115(10):
- Zhu, M, et al., Mol Neurobiol, 2016. 53(4):
- Wang, X, et al., Alzheimers Dement, 2015. 11(1):
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- Claria, J, et al., Mol Aspects Med, 2017.
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- Chiu, CY, et al., Inflamm Res, 2012. 61(9):
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