Did you know Chronic inflammatory diseases have reached epidemic levels in industrialised countries. According to the 2014-2015 National Health Survey, half of all Australians live with a chronic inflammatory disease such as asthma, cardiovascular disease, diabetes mellitus, obesity, arthritis, Alzheimer’s disease, autoimmune disease, and cancer.4, 5, 6
It was long assumed that an acute inflammatory process was passively self-limiting, with chemotactic factors (substances that stimulate the migration of inflammatory cytokines) simply diluting or draining away.7 However this is not the case, evidenced by the development of chronic inflammatory conditions, where inflammatory mediators persist at a site, and the resolution of the inflammatory process failing to engage.8
It is now known that the resolution of inflammation is an active process, controlled by a family of chemicals known as specialised pro-resolving mediators (SPMs).9 SPMs promote inflammation resolution, reduce pain, encourage the clearance of pathogens and mitigate pathological inflammation, without immunosuppression. Together, these qualities make SPMs an important consideration for the treatment of chronic, unremitting inflammatory conditions.
SPMs are derivatives of omega-3 essential fatty acids (EFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). They are produced during the resolution phase of an acute inflammatory response, working to switch off the inflammatory process.10, 11 Several classes of SPMs are derived from EFAs, including resolvins (e.g. RvE, RvD1), protectins (e.g. PD1), and maresins (e.g.MaR1, HDHA).12 Lipoxins, another class of SPMs, are produced from the omega-6 fatty acid, arachidonic acid.
At the genesis of these inflammatory states is an initial insult, such as a tissue injury, infection, or exposure to an allergen or toxin, which activates the acute inflammatory response.13, 14 Here, an influx of poly-morpho-nuclear neutrophils (PMNs) enter the affected site and produce inflammatory mediators (e.g. cytokines, chemokines and eicosanoids) needed to trigger tissue repair. PMNs also phagocytose pathogens, and finally themselves undergo apoptosis,15, 16 causing inflammation and tissue damage, which must be cleared by macrophages in a process known as efferocytosis. Clearing this cellular debris enacts the resolution of the inflammatory process,17 allowing the body to once again return to homeostasis.
SPMs: inflammation stop signs
Entering this stage of inflammatory resolution relies on the synthesis of SPMs, which reduce PMN infiltration and increase efferocytosis.18 SPMs also achieve resolution via the regulation of macrophage polarisation. Macrophages exist in two broad phenotypes; M1 macrophages, which are pro-inflammatory, and M2 macrophages, which synthesise SMPs, inhibit PMNs, and promote efferocytosis, tissue repair, and resolution. SPMs trigger the macrophage switch from the M1 to the M2 phenotype, thereby promoting resolution.19
Additionally, SPMs have specific anti-inflammatory mechanisms, decreasing pro-inflammatory and increasing anti-inflammatory mediator production.20 In animal models, resolvins demonstrate the ability to reduce the production of pro-inflammatory eicosanoids and cytokines such as prostaglandin E2 (PGE2), leukotriene B4 (LTB4), interleukin-1β (IL-1β), IL-17 and IL-6.21, 22 Resolvins have also been shown to inhibit tumour necrosis factor alpha (TNF-α) activation in vitro and in animal models.23 SPMs also counter-regulate inflammatory gene transcription, and increase the clearance of inflammatory mediators by up-regulating chemokine binding receptors on T cells and PMNs, which are then phagocytosed by macrophages.24 However, in patients experiencing chronic inflammatory conditions, SPM production can be compromised,25 preventing the resolution of their condition. Supporting their presentation with Specialised Pro-Resolving Mediators will therefore provide the body with the capacity to work toward resolution of their inflammation.
Reduce the pain too, please
Additionally, SPMs also carry standalone analgesic properties. Shown to influence signalling within the brain, the resolvin RvE1 has demonstrated capacity to inhibit glutamate release and N-methyl-D-aspartate (NMDA) receptor hyperactivity, both important targets for pain relief.26 Exhibited further in animal models of inflammatory pain, resolvins have reduced pain-associated behaviours, and produced comparable pain relieving effects to the pharmaceutical medication pregabalin.28 Whilst reducing inflammation can also provide pain relief, these additional analgesic effects of SPMs will be of particular benefit for those patients experiencing concomitant chronic pain.
The many patients of SPMs
Given their pro-resolving and anti-inflammatory actions, SPMs are indicated in any condition involving chronic, unremitting inflammation. One such example commonly presenting in clinical practice is arthritis, with the crucial role of SPMs in this condition demonstrated in several human and animal studies.29, 30, 31, 32 Beyond this, Table 1 explores further evidence-based applications of SPMs in a varying range of inflammatory conditions.
Table 1. Overview of emerging research and applications for SPMs.
||SPM mediator studied
||RvD1 and 17-HDHA
||Inhibited immunoglobulin E (IgE) production and suppressed differentiation of naïve B cells into IgE secreting cells in vitro.33
||RvD1 and 17(R)-RvD1
||Reduced severity of vaginal hyperalgesia and reduced vascular permeability in endometrial cysts in rat model of endometriosis.34
||Potently suppressed inflammatory cell infiltration and reduced expression of IL-23 in skin and dendritic cells in mouse model of psoriatic dermatitis.35
||RvD1, RvD2 and RvE1
||Inhibited neutrophil migration and accelerated wound healing in mouse model; RvE1 was most effective, and caused more mature collagen organisation and reepithelialisation.36
||RvD1, RvD2 and RvE1
||Inhibited debris-stimulated cancer progression by enhancing macrophage phagocytosis in mouse models.37
||Down-regulated Sjögren’s syndrome associated inflammatory genes and reduced apoptosis in Sjögren’s syndrome mouse model.38
|Periodontitis associated bone loss
||Modulated gene expression, favouring bone preservation, and down-regulated interferon gamma (IFN-γ) without dampening Porphyromonas gingivalis specific immune response in mice.39
||Reduced atherosclerotic lesion size, the formation of severe lesions, and the expression of pro-atherogenic genes in mice.40
|Inflammatory bowel disease
||RvD2, AT-RvD1, MaR1, and 17-HDHA
||Have been shown to help reduce intestinal tissue damage, reduce inflammation and neutrophil infiltration, maintain body weight, and increase survival in animal models of inflammatory bowel disease.41, 42, 43
SPMs and EFAs are allies
It is important to note that although EPA and DHA are precursors of SPMs, EFAs do not possess the same unique pro-resolving qualities.44 Additionally, during states of chronic inflammation,45 and with progressive ageing,46 the body’s capacity to convert EFAs into SPMs may be compromised. This is a potential explanation for why fish oil, while reducing inflammation, may not always be clinically efficacious in fully resolving established inflammatory states. Therefore, SPMs do not replace EFA therapy, and vice versa – their actions are distinct but complementary. EFA supplementation should be utilised to correct deficient dietary intake, during times of increased demand (e.g. pregnancy) and to influence the induction of the acute inflammatory cascade (preventing the development of chronic inflammation). Meanwhile, providing Specialised Pro-Resolving Mediators augments the resolution of chronic inflammatory conditions, given its targeted action in resolving chronic, unremitting inflammation. For the chronically inflamed patient, EFAs and SPMs are ideally prescribed together to resolve existing inflammation, and prevent the development of inflammation in the future.
The reality that chronic inflammatory conditions have now reached epidemic proportions is evidenced via patients’ presentation in clinical practice. Whilst resolution of these states can often present a clinical challenge, Specialised Pro-Resolving Mediators now offer an innovative and unique solution. These lipid mediators promote the resolution of chronic, unremitting inflammation, whilst also carrying their own unique anti-inflammatory and analgesic properties. Complementing EFAs which supplement dietary intake and prevent the development of chronic inflammation, SPMs offer hope and freedom for many inflamed patients.