Specialised pro-resolving lipid mediators
Acute inflammatory response due to injury or infection is a self-limiting process. Initially, pro-inflammatory lipid mediators derived from the omega-6 fatty acid (FA) arachidonic acid (AA), prostaglandins and leukotrienes play an important role. Acute inflammatory reaction is characterised by the build-up of polymorphonuclear leukocytes (PMN), followed by monocytes and macrophages. These self-limiting events occur together with the release of local factors that prevent excessive leukocyte traffic. Complete resolution of acute inflammation and the return to tissues homeostasis are necessary to prevent progression to chronic inflammation, which underlies many diseases (arthritis, periodontal disease, cardiovascular disease, etc.) and which is considered the result of excessive pro-inflammatory mediators.
New classes of autacoids involved in the inflammation resolution process have been identified: lipoxins, E and D series resolvins, protectins and maresins. These specialised pro-resolving lipid mediators (SPMs) prevent excessive inflammation and promote microbe and apoptotic cell elimination, favouring resolution and the return to tissue homeostasis. Identification of these SPMs and the biochemical mechanisms and cellular processes involved have changed the perception of acute inflammation resolution from a passive process to an active, programmed tissue process. Aspirin triggers biosynthesis of SPMs.
Lipoxins, AA-derived lipoxygenases, are anti-inflammatory and were the first pro-resolving mediators to be identified. They signal macrophages to favour absorption of the rest of the neutrophils; fundamentally, they limit recruitment and adhesion of PMN.
Omega-3 polyunsaturated fatty acids (n-3 PUFA), in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are SPM precursors. EPA-derived mediators linked to potent biological effects are termed E-series (E-series resolvins, RvE) while those biosynthesised from the DHA precursor are termed D-series resolvins (RvD). Bioactive compounds from DHA that transport triene structures (docosatrienes) and which have immunoregulatory properties are termed protectins, while those generated inside nerve tissue are termed neuroprotectins (NPD).
The potent anti-inflammatory and immunoregulatory actions of resolvins include blocking pro-inflammatory mediator production and regulating leukocyte traffic. They detain PMN infiltration and transmigration, as well as cytokine expression.
Protectins are synthesised via a different pathway. They also detain PMN infiltration and cytokine expression.
Maresins (macrophage mediators in resolving inflammation, MaR) are the most recently identified SPMs. They are produced by macrophages and regulate the latter’s response as well as that of neutrophils.
Many current anti-inflammatory treatments target enzyme inhibition and/or pro-inflammatory receptor antagonism (such as selective cyclo-oxigenase inhibitors and anti-tumour necrosis factor-α (TNF-α) drugs). The new conception of inflammation resolution as an active process opens up the possibility of using endogenous agonists to stimulate resolution naturally. Both endogenous production and administration of pro-resolving lipid mediators can accelerate resolution and the return to homeostasis.
Resolvins and protectins have been shown to have a very potent action when administered in animal models of human inflammatory diseases (colitis, peritonitis, dermal inflammation, asthma and eye diseases). RvE1 reduces oral infectious inflammation and associated bone loss, inhibits adenosine diphosphate-dependent platelet aggregation and regulates dendritic cells and effector T-cells. And in the first study on humans, a resolvin analogue effectively reduced symptoms of dry eye syndrome. All this indicates that in humans, SPMs could be useful in the treatment of inflammatory disorders.
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