Specialised pro-resolving mediators of inflammation in inflammatory arthritis
Introduction
Specialised pro-resolving mediators (SPM) are a family of oxylipids that include resolvins, protectins, maresins and lipoxins. SPM contribute actively to the resolution of inflammation through engagement, at nanomolar concentrations, of cognate G-protein coupled receptors [1]. SPM arise from n-3 long chain polyunsaturated fatty acids (n-3FA) through the action of lipoxygenase enzymes and other remodelling steps [2]. The lipoxins are formed from arachidonic acid (AA, 20:4 n-6) [1], [3] but there is particular interest in SPM derived from eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3). The E-series resolvins, (RvE1-E3) are formed from EPA via a hydroxyl intermediate 18-hydroxyeicosapentaenoic acid (18-HEPE) and initially require acetylated COX-2 or cytochrome P450. 18-HEPE is then converted by 5-lipoxygenase to RvE1, RvE2 or by 15-lipoxygenase to RvE3 [4], [5] (Fig. 1). DHA can be metabolised by acetylated COX-2 or 15-lipoxygenase, to the unstable intermediate 17-hydroperoxydocosahexaenoic acid (17-HpDHA) that can form protectin D1 (PD1), 10S,17S-dihydroxydocosahexaenoic acid (10S,17S-DHDHA) and 17-hydroxydocosahexaenoic acid (17-HDHA). The D-series resolvins (RvD1–RvD6) form as a result of metabolism of 17-HDHA by 5-lipoxygenase [6] (Fig. 1). In humans, the maresins are formed by metabolism of DHA by macrophage 12-lipoxygenase giving rise to 14-hydroxydocosahexaenoic acid (14-HDHA) and maresin-1 (MaR-1) [7] [8] (Fig. 1).
Fish oils are a rich source of EPA and DHA, that have been shown to enhance management of rheumatoid arthritis (RA) [9] and systemic lupus [10], [11] and to reduce reoccurrence rates in Crohn׳s disease in patients who are at high risk for relapse [12]. While a number of potential anti-inflammatory actions of n-3FA have been identified [13], it is conceivable that conversion of EPA and DHA to SPM could be a significant contributor to the disease mitigating effects of fish oil in inflammatory diseases. However, in spite of animal studies, which have demonstrated the presence of SPM in experimentally-induced inflammation [14], [15] and the demonstration of SPM in healthy subjects taking fish oil [3], reports regarding SPM in human arthropathies are confined to a limited exploratory analysis of a small number of synovial fluid samples [16].
Based on favourable results of randomised controlled trials [17], at the Royal Adelaide Hospital patients with inflammatory arthropathies are routinely given advice to take fish oil supplements in addition to disease-modifying anti-inflammatory drugs. This study was undertaken to determine whether SPM are present in chronic inflammatory knee effusions of patients with arthritis of various aetiologies, to examine how well plasma SPM concentrations reflected those of synovial fluid from the inflamed joint, and to compare plasma SPM concentrations in patients with arthritis with those of healthy controls taking n-3FA.
Section snippets
Arthritic patients
All patients gave informed written consent and the study protocol was approved by the Human Research Ethics Committee, Royal Adelaide Hospital. All procedures were performed in accordance with the Declaration of Helsinki. Synovial fluid and peripheral blood samples were obtained contemporaneously from 36 patients undergoing arthrocentesis of an inflammatory knee effusion. Most patients had been told previously to take n-3FA as fish oil 10–15 mL daily as a complement to therapy with
Results
The characteristics of the patients are shown in Table 1. Thirty three of the patients were taking n-3 FA as fish oil supplements in stated doses ranging from 4 to 28 g daily; (mean intake 11 g, median 11 g, IQR 6.4 g, 14 g). The duration of fish oil intake varied from 1 month to 12 years (mean 4 yrs, median 4 yrs, IQR 3 months, 6 yrs). The synovial fluid levels of EPA and DHA were 3.5±0.5% and 5.4±0.3% of total phospholipid fatty acids, respectively, and corresponding plasma levels were EPA 4.5±0.6%
Discussion
This is the first study to comprehensively measure a range of SPM in synovial fluid and plasma of arthritis patients taking n-3FA and healthy volunteers of similar age and gender. We have shown that a broad spectrum of SPM derived from both EPA and DHA are present in synovial fluid and plasma of patients taking n-3FA for arthritis. A large number of SPM in plasma and synovial fluid were negatively correlated with ESR a marker of inflammation that associates with severity of arthritis. Synovial
Authors’ contributions
AEB was responsible for recruitment and collection of samples from healthy controls, writing the manuscript and assisting with statistical analysis.
MM was involved in design of the study, collection and preparation of samples from patients with inflammatory arthritis, collection and interpretation of initial data and revising the manuscript.
EM was responsible for assaying the specialised proresolving mediators of inflammation in the study interpreting data and revising the manuscript.
MP was
Conflict of interest
None of the authors has any competing interests to declare.
Acknowledgements
This work was supported by a grant-in-aid from Arthritis Australia and a project grant from the National Heart Foundation of Australia.
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