RESOLVINS AND PROTECTINS

Chemistry and Biology

formula The omega-3 essential fatty acids are currently the focus of considerable interest among nutritionists, because of a large number of potential beneficial effects for consumers. The mechanisms by which such effects are exerted is still a matter for controversy, but is seems likely that oxygenated metabolites derived from eicosapentaenoic acid (20:5(n-3) or EPA) and docosahexaenoic acid (22:6(n-3) or DHA), the ‘resolvins’ or ‘docosatrienes’, must play a significant part as they have potent anti-inflammatory and immunoregulatory actions at concentrations in the nanomolar and picomolar range. The term resolvin was coined by Professor Charles N. Serhan and colleagues because these compounds were first encountered in resolving inflammatory exudates. Compounds derived from EPA are designated as resolvins of the E series, while those formed from the precursor DHA are denoted as either resolvins or protectins (formerly 'neuroprotectins') of the D series.

1. 18R Resolvins of the E Series

Biosynthesis of the 18R resolvins of the E series has elements in common with the synthesis of the epi-lipoxins and leukotrienes.

formula

In vascular endothelial cells derived from blood vessels, the cyclooxygenase enzyme COX2 that has been acetylated by aspirin introduces an 18R hydroperoxy-group into the EPA molecule (c.f. the role of aspirin in the biosynthesis of the epi-lipoxins). This is reduced to the corresponding hydroxy compound before a 5S-hydroperoxy group is introduced into the molecule, presumably by the action of 5-lipoxygenase as in the biosynthesis of the leukotrienes. A further reduction step produces 15S,18R-dihydroxy-EPE or resolvin E2. Alternatively, the 5S-hydroperoxy,18R-hydroxy-EPE intermediate is converted to a 5,6-epoxy fatty acid in polymorphonuclear neutrophils in humans and eventually to 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid or resolvin E1 by process similar to the formation of leukotrienes in leukocytes.

The highly specific stereochemistry of resolvin E1 is required for activation of a ligand-specific receptor and thence for its biological activity down to picomolar concentrations.

2. 17R- and 17S-Resolvins and Protectins of the D Series

DHA is converted to 17R-resolvins by a similar aspirin-triggered COX2 mechanism to the previous. In the absence of aspirin, COX2 in human microvascular endothelial cells converts DHA to 13S-hydroxy-DHA.

In an alternative reaction in the absence of aspirin, a lipoxygenase generates 17S-hydroxy-DHA as the initial product. This is converted to 7S-hydroperoxy,17S-hydroxy-DHA by the action of a lipoxygenase, and thence via an epoxy intermediate to epimeric resolvin (RvD1 or 7S,8R,17S-trihydroxy-docosa-4Z,9E,11E,13Z,15E,19Z-hexaenoic acid ) and resolvin D2 (RvD2 or 7S,16,17S-trihydroxy-docosa-4Z,8E,10Z,12E,14E,19Z-hexaenoic acid ).

Resolvins D1 and D2 - formulae

An alternative lipoxygenase-generated intermediate from aspirin-triggered 17R-hydroxy-DHA, i.e. 4S-hydroperoxy,17R-hydroxy-DHA, is transformed via an epoxide to epimeric resolvins D3 and D4. Again, there are parallels in the biosynthesis of resolvins (and protectins) with that of epi-lipoxins (aspirin-triggered lipoxins) from arachidonate.

3. Protectins (Neuroprotectins)

In studies of resolvin formation in brain tissue in response to aspirin treatment, it was shown that new docosatrienes termed initially ‘neuroprotectins’ were produced. As it is now recognized that the formation and actions of these docosanoids are not restricted to neuronal tissue, it has been suggested that the simpler term ‘protectins’ is preferable. The biosynthetic pathway to neuroprotectin or protectin in brain tissue is illustrated below. The lipoxygenase product 17S-hydroperoxy-DHA is converted first to a 16(17)-epoxide and then to the 10,17-dihydroxy docosatriene (10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid), denoted as 10R,17S-DT or PD1 (or NPD1). As with the leukotrienes, there are three double bonds in conjugation, hence the term ‘triene’, though there are six double bonds in total. Again, it appears that this highly stereospecific structure is essential for biological activity.

protectin biosynthesis

4. Biological Activity

The resolvins and neuroprotectins are distinctive and highly stereospecific lipids, which are endogenous local mediators with strong anti-inflammatory effects in addition to some immunoregulatory activities at picomolar to nanomolar concentrations. They are part of the molecular mechanisms that contribute to removal of inflammatory cells and restoration of tissue integrity once the need for the inflammatory response is over. It is evident that the presence of aspirin uniquely facilitates the resolution of inflammation. Thus, at local sites of inflammation, aspirin treatment enhances the conversion of the omega-3 fatty acids EPA and DHA to 18R-oxygenated products, i.e. resolvins of the E and D series, which carry potent anti-inflammatory signals. So far one receptor has been identified that mediates these activities.

During inflammation, polymorphonuclear neutrophils are produced which have generally beneficial effects in countering disease, but in the longer term or if malfunctioning they may eventually cause trauma and tissue damage through infiltration into tissues. The resolvins, like the lipoxins, appear to have an important role in regulating and indeed inhibiting these harmful effects. In so doing they oppose the effects of some of the pro-inflammatory prostanoids. For example, nanomolar concentrations of resolvin E1 dramatically reduced dermal inflammation, peritonitis, dendritic cell migration and interleukin production. The 17S-resolvins appear to have very similar functions to those of the 18R-series, while the (neuro)protectins appear to operate in the same way in brain tissue. In addition, (N)PD1 protects retinal epithelial cells from apoptosis induced by oxidative stress, and it has protective effects in animal models of stroke and of Alzheimer's disease. Amongst its activities in non-neuronal tissues, it promotes apoptosis of T cells. It is evident that such compounds and their metabolism have considerable potential for therapeutic intervention in acute inflammation or chronic inflammatory disease.

Resolvin E1 is eventually de-activated in tissues by oxidation to 18-oxo-RvE1, and it is catabolized following omega-hydroxylation.

From a nutritional or health standpoint, it has been suggested that dietary supplements of omega-3 fatty acids, taken together with aspirin, may reduce the clinical symptoms of many disease states, including inflammatory disorders, cardiovascular disease and cancer.

The Lipid Library