Even though we need and cannot survive without this finely-tuned set of complex processes that protect us from infectious and non-infectious stressors, we also need inflammation to subside when no longer needed, in order for tissues to heal, cellular debris to be cleaned, and homeostasis to be restored.
Instead, when chronic inflammation is uncontrolled, what started out as our greatest ally can become our worst enemy, and this is what's now becoming the norm. It is widely recognised that many of the common chronic diseases that are so prevalent in our modern world have chronic inflammation as a major underlying cause.
In this article, NutriAdvanced delves deeper into inflammation, how our understanding of the factors that affect the transition from acute to chronic has progressed and the role specialised pro-resolving mediators play in this interesting tale.
Acute inflammation
The acute inflammatory response is part of the body’s innate defence, triggered when a potential infectious or non-infectious threat is encountered such as bacteria, virus, parasite or fungi, damaged barrier (skin, gut etc.), injury or wound, toxin, foreign object (dirt, splinter etc.) or allergen. It is immediate and non-specific, characterised by the release of pro-inflammatory mediators to stimulate increased blood flow and vascular permeability, which enables the movement of plasma and leukocytes (such as neutrophils and macrophages) from the blood to the injured or affected tissues. The five cardinal signs of inflammation are heat, redness, swelling, pain and loss of function.
The crucial importance of resolution
The inflammatory response promotes the repair of damaged tissues and the elimination of harmful stressors. It is normally protective and self-limited, leading to the complete resolution of leukocyte infiltrates (eg neutrophils and macrophages) and the clearance of cellular debris and microbes so that homeostasis can be restored.
Inflammation resolution is critically important. As an example, when leukocytes such as neutrophils and macrophages enter a site of injury or infection as part of the inflammation initiation phase, they have a vitally protective role to play – they secrete factors that kill and degrade pathogens and they are also able to remove pathogens by phagocytosis. However, they can also cause collateral tissue damage by their ability to inadvertently release harmful agents such as reactive oxygen species and lysosomal enzymes when they congregate excessively. It is important therefore that they subside once no longer needed, thus minimising any collateral damage. The resolution phase - where acute inflammation abates, tissues are repaired, cellular debris is cleared and homeostasis is restored - is vitally important to prevent the switch from acute to chronic inflammation. The five cardinal signs of resolution are removal, restoration, regeneration, remission and relief. It is now widely accepted that impaired or dysregulated inflammation resolution underlies a growing list of chronic inflammatory diseases.
Professor Charles Serhan, PhD, DSc, Harvard Medical School and Brigham and Women’s Hospital, a prominent researcher in the field of inflammation resolution has carried out extensive research on the critical importance of this phase, he wrote;
“The resolution of inflammation is central to human health and its potential failure lies at the heart of many diseases where uncontrolled inflammation amplifies as well as creates illness.”
Resolution is an active, not passive process
The resolution phase of inflammation has long been appreciated as an important part of calming inflammatory processes and restoring homeostasis. The resolution phase was also long believed to be a passive process, however, in the last 20 years or so, researchers led by Professor Charles Serhan, have demonstrated that resolution of self-limited inflammation is actually an active process. We now know that inflammation doesn’t just fade away on its own; the body actively shuts it down using ‘stop’ signals.
“Although resolution of disease is appreciated by clinicians, resolution was considered a passive process until our contributions, and now many other worldwide, to obtain new evidence demonstrating that resolution of self-limited inflammation is an active process.” ~ Professor Charles Serhan
SPMs – Inflammation’s ‘stop’ signals
And this is when the progression in understanding of inflammation resolution really started to gather pace. Now, not only have researchers, led by Professor Serhan, demonstrated that inflammation resolution is an active (not passive) process, but they have also identified a super-family of around 28 chemical mediators that are widely recognised as inflammation’s ‘stop’ signals. This superfamily of ‘stop’ signals is collectively known as specialised pro-resolving mediators; commonly referred to as SPMs. SPMs are not in any way suppressive of the inflammatory response; instead, they support inflammation resolution by limiting the magnitude and duration of the acute inflammatory response.
‘Pro-resolution’ does not equal ‘anti-inflammatory’
It is important to distinguish between ‘anti-inflammatory’ and ‘pro-resolution’. Conventional anti-inflammatory medication such as non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the amplitude of the initiation phase of the inflammatory response but the vast majority do not resolve inflammation. In contrast, specialised pro-resolving mediators (SPMs) are produced by the body, not for ‘anti-inflammatory’ activity, rather they are ‘pro-resolution’ chemical mediators.
Specialised pro-resolving mediators (SPMs):
- Lipid mediators derived from polyunsaturated fatty acids (PUFAs)
- Lipoxins, protectins, maresins, resolvins and more
- Produced at the inflammatory site after the inflammation initiation phase
- Function in host defence including promoting anti-viral B cell antibodies and other white blood cell activity
- Stimulate clearance of cellular debris and reduce pro-inflammatory cytokine levels
- Agonists of resolution – they stimulate resolution of inflammation and reduce pain
- Accelerate homeostasis, protect organs and regenerate tissues
The SPM Superfamily
Several classes of SPMs have now been identified that work together in a coordinated approach to resolve inflammation. Some of these include resolvins, maresins, lipoxins, and protectins. SPMs are produced in the body from long-chain polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) via a series of enzyme steps. Low dietary intake of omega 3 PUFAs, biological ageing, sedentariness, obesity and chronic illness may all negatively impact the body’s natural production of SPMs. This highlights just how crucial it is to ensure long-chain omega 3 PUFAs are regularly included in the diet.
Omega 3 PUFAs & SPMs
There are many different classes and types of SPMs, produced in the body from long-chain PUFAs:
- Eicosapentaenoic acid (EPA) can be converted to 18-hydroxyeicosapentaenoic acid (18-HEPE) which is an intermediate precursor to a group of SPMs called E-series resolvins.
- Docosahexaenoic acid (DHA) can be converted to 17-hydroxydocosahexaenoic acid (17-HDHA) which is an intermediate precursor to a group of SPMs called D-series resolvins.
- Docosahexaenoic acid (DHA) can be converted to 14-hydroxydocosahexaenoic acid (14-HDHA) which is an intermediate precursor to a group of SPMs called
SPMs help us to ‘bounce back’ from inflammation stressors
Dysregulation of the resolution phase, including reduced production of SPMs may lead to uncontrolled or chronic low-grade inflammation characterised by an excessive intensity of the inflammatory response and insufficient resolution, causing pain, tissue damage and destruction. SPMs are critical for our ability to ‘bounce back’ from inflammation stressors. Dysregulated resolution leads to reduced ‘inflammation resilience’.
Reduced SPMs in many common chronic inflammatory conditions
Much human research has now found reduced levels of SPMs in a wide range of chronic and painful inflammatory conditions that have become so common in our modern world. Reduced levels of SPMs are also associated with obesity and ageing. Both obesity and ageing are characterised by chronic low-grade inflammation. Surgery is also associated with reduced levels of SPMs.
SPMs & Covid-19
SPMs are also being studied for their potential role in Covid-19. Back in 2020, Professor Charles Serhan co-authored a peer-reviewed paper that highlighted the potential for SPMs in addressing pro-inflammatory cytokine production and cytokine storm in Covid-19.
How to support SPMs:
- Optimise intake of omega 3 PUFAs EPA & DHA through diet and or high-quality omega 3 supplementation.
- Consider supplementation with omega 3 PUFAs EPA & DHA enriched with SPM precursors 18-hydroxyeicosapentaenoic acid (18-HEPE), 17-hydroxydocosahexaenoic acid (17-HDHA) and 14-hydroxydocosahexaenoic acid (14-HDHA).
Who may benefit from enriched omega 3?
- Chronic inflammation
- Auto-immune
- Chronic pain