Immuno-Resolving Ability of Resolvins, Protectins, and Maresins Derived from Omega-3 Fatty Acids in Metabolic Syndrome.

Omega-3 fatty acid consumption has been suggested to be beneficial for the prevention of type 2 diabetes mellitus (T2DM). Its effects have been attributed to anti-inflammatory activity, with the inhibition of arachidonic acid metabolism playing a central role. However, a more recent view is that omega-3 fatty acids play an active role as the precursors of potent, specialized pro-resolving mediators (SPMs), such as resolvins, protectins, and maresins. Docosahexaenoic acid (DHA)- and eicosapentaenoic-acid-derived SPMs are identified in the adipose tissue but the levels of certain SPMs (e.g., protectin D1) are markedly reduced with obesity, suggesting adipose SPM deficiency, potentially resulting in unresolved inflammation. Supplementation of the biosynthetic intermediates of SPM (e.g., 17-hydroxy-DHA) or omega-3 fatty acids increases the level of adipose SPMs, reduces adipose inflammation (decrease in macrophage accumulation and change to less inflammatory macrophages), and enhances insulin sensitivity. The findings from studies using rodent obesity models must be translated to humans. It will be important to further elucidate the underlying mechanisms by which obesity reduces the levels of and the sensitivity to SPM in adipose tissues. This will enable the development of nutrition therapy to enhance the effects of omega-3 fatty acids in the prevention and/or treatment of T2DM.

The roles of omega-3 fatty acids and resolvins in allergic conjunctivitis.

PURPOSE OF REVIEW: Lipids are one of the most important constituents in our body. Advances of lipidomics are elucidating the new roles of various lipid molecules in allergic diseases. For example, some reports showed anti-inflammatory effects of omega-3 fatty acids (FAs), such as docosahexaenoic acid, eicosapentaenoic acid, and their metabolites, on allergic diseases. Here, we introduce the role of lipid mediators in allergic conjunctivitis mouse model. RECENT FINDINGS: Lipidomics using liquid chromatography-tandem mass spectrometry can profile numerous lipid molecules from small tissue samples such as conjunctival specimens. Lipidomics analysis showed that various inflammatory lipid mediators are produced in the conjunctival tissue of allergic conjunctivitis mouse model. Dietary omega-3 FAs reduced these inflammatory lipid mediators in the conjunctiva and alleviated allergic conjunctivitis symptoms in mouse models. In addition, the roles of specialized proresolving lipid mediators (SPMs) have been reported for allergic inflammation. SUMMARY: Lipid mediators have important roles for the pathophysiology of the allergic diseases including allergic conjunctivitis. Omega-3 FAs and SPMs are expected as new treatment tools for allergic conjunctivitis.

Effect of omega-3 fatty acid supplementation on resolvin (RvE1)-mediated suppression of inflammation in a mouse model of asthma.

Objective: ResolvinE1 (RvE1), an endogenous lipid mediator derived from omega 3 fatty acids contributes to resolution of allergic inflammatory responses. We investigated effects of RvE1 (R) and omega 3 fatty acids (O) on airway reactivity and inflammation using allergic mice. Methods: Mice were divided into control (nonasthmatic; CON) and allergen sensitized-challenged (asthmatic; SEN) groups, and were sensitized i.p. on days 1, 6 with 0.2 µg ovalbumin (OVA) followed by 5% OVA aerosol challenges on days 11-13. RvE1 was administered i.p. postallergen challenge, while omega 3 fatty acids (fish oil) were administered via oral gavage once daily (days 1-13). Whole body plethysmography and bronchoalveolar lavage (BAL) studies were performed on day 14. Results: RvE1 attenuated airway responsiveness to methacholine (48 mg/ml) in treated asthmatic mice vs. nontreated (150 ± 27.88% in SEN vs. 54 ± 7.52% in SEN + R, p < .05). No difference was observed with omega-3 supplementation (115 ± 19.28% in SEN + O) or treatment with both RvE1 and omega 3 fatty acids (39 ± 12.37% in SEN + R + O vs. 54 ± 7.52% in SEN + R). Differential BAL cell analysis showed that RvE1 decreased eosinophils and neutrophils in SEN mice (p < .005) while no difference was observed with omega-3 fatty acids. SEN + R + O group had similar results as RvE1 treated mice, suggesting that only RvE1 attenuated inflammation. Conclusions: RvE1 attenuated airway responsiveness and inflammation in asthmatic mice. Omega-3 fatty acids, although a precursor for RvE1 formation, had no additive effects on RvE1 decreases in airway inflammation and airway reactivity. Our data suggests that omega-3 supplementation has little effect on airway inflammation and reactivity in our model of asthma.

Fish Oil Increases Specialized Pro-resolving Lipid Mediators in PAD (The OMEGA-PAD II Trial).

BACKGROUND: N-3 polyunsaturated fatty acid (PUFA) supplementation has been associated with reduced mortality and inflammation in patients with cardiovascular disease. There are limited data on the effects of n-3 PUFA supplementation in patients with peripheral artery disease (PAD). MATERIALS AND METHODS: The OMEGA-PAD II trial was a double-blinded, randomized, placebo-controlled trial to assess the effect of 3 mo of high-dose oral n-3 PUFA supplementation on inflammation, endothelial function, and walking ability in patients with PAD. RESULTS: Twenty-four patients with claudication received 4.4 g/d of fish oil or placebo for 3 mo. Outcomes measured included high-sensitivity C-reactive protein levels, the omega-3 index, endothelial function as measured via flow-mediated vasodilation, walking impairment questionnaire, and a 6-min walk test. Plasma levels of specialized pro-resolving lipid mediators (SPMs) were measured by liquid-chromatography-tandem mass spectrometry. In patients treated with fish oil, the absolute mean omega-3 index significantly increased from baseline (fish oil: 7.2 ± 1.2%, P < 0.001; placebo: -0.4 ± 0.9%, P = 0.31; between-group P < 0.001). Furthermore, there were significant increases in several pathway markers of SPM biosynthesis, including several mono-hydroxyeicosapentaenoic acids and mono-hydroxydocosahexaenoic acids. We also observed significant increases in the SPM lipoxin A5 (fish oil: 0.57 ± 0.70 pg/mL, P = 0.05; placebo: 0.01 ± 0.38 pg/mL, P = 0.93; between-group P = 0.04) and resolvin E3 (fish oil: 154 ± 171 pg/mL, P = 0.04; placebo: 32 ± 54 pg/mL, P = 0.08; between-group P = 0.04). There were no significant changes in high-sensitivity C-reactive protein, flow-mediated vasodilation, walking impairment questionnaire, or 6-min walk test in the fish oil group. CONCLUSIONS: Fish oil increases SPMs in plasma of patients with PAD. Further studies are required to determine whether these early changes translate to clinical improvements in patients with PAD.

The immunomodulatory effects of fish-oil supplementation in elite paddlers: A pilot randomized double blind placebo-controlled trial.

BACKGROUND: Physical exercise can induce imbalance of different cytokines by leading them towards an inflammatory and immunosuppressive milieu. Fish-oil (FO) supplementation may modulate the mentioned skewed balance following intense exercise. Therefore, we decided to investigate the effect of intense physical exercise and FO supplementation on cytokine production and helper T (Th) cell phenotype in male elite paddlers. SUBJECTS AND METHODS: Male elite paddlers consumed 6 g/day of either FO capsules (n=11) containing 3.6 g long chain n-3 polyunsaturated fatty acids (1.2 g docosahexaenoic acid and 2.4 g eicosapentaenoic acid) or placebo capsules (n=11) for 4 weeks. The paddlers simultaneously undertook a program of increasing exercise. Blood samples were taken from all the subjects 48 h before and after the 4 weeks of supplementation. RESULTS: Our results show that while FO supplementation decreases the production of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in the elite paddlers, it increases the production of IL-6. On the other hand, while there was no change in IL-4 secretion, the production of interferon (IFN)-γ was significantly decreased after 4 weeks FO consumption. We also showed that the production of IL-10 was significantly higher in the FO group compared to the placebo. Finally, we found that fish-oil consumption shifts the balance between Th cells towards Th2 phenotype during intensive exercise. CONCLUSION: Our results suggest that the consumption of n-3 polyunsaturated fatty acids during intense exercise can induce the anti-inflammatory and immunosuppressive cytokine networks that are associated with a reduced Th1/Th2 ratio in elite paddlers.

Dendritic cell activation, phagocytosis and CD69 expression on cognate T cells are suppressed by n-3 long-chain polyunsaturated fatty acids.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are bioactive n-3 long-chain polyunsaturated fatty acids (LCPUFAs) in fish oil that exert immunosuppressive effects. A significant amount of literature shows that n-3 LCPUFAs suppress dendritic cell (DC) function in vitro; however, few studies have determined if the effects are emulated at the animal level. In this study, we first focused on the functional consequences of 5% (weight/weight) fish oil on splenic CD11c(+) DCs. Administration of n-3 LCPUFAs, modelling human pharmacological intake (2% of total kcal from EPA,1·3% from DHA), to C57BL/6 mice for 3 weeks reduced DC surface expression of CD80 by 14% and tumour necrosis factor-α secretion by 29% upon lipopolysaccharide stimulation relative to a control diet. The n-3 LCPUFAs also significantly decreased CD11c(+) surface expression and phagocytosis by 12% compared with the control diet. Antigen presentation studies revealed a 22% decrease in CD69 surface expression on transgenic CD4(+) T lymphocytes activated by DCs from mice fed fish oil. We then determined if the functional changes were mechanistically associated with changes in lipid microdomain clustering or plasma membrane microviscosity with n-3 LCPUFAs, as reported for B and T lymphocytes. Fish oil administration to mice did not influence cholera-toxin induced lipid microdomain clustering or microviscosity, even though EPA and DHA levels were significantly elevated relative to the control diet. Overall, our data show that n-3 LCPUFAs exert immunosuppressive effects on DCs, validating in vitro studies. The results also show that DC microdomain clustering and microviscosity were not changed by the n-3 LCPUFA intervention used in this study.

Nutrigenetic response to omega-3 fatty acids in obese asthmatics (NOOA): rationale and methods.

Uncontrolled asthma is a major cause of hospitalizations and emergency room visits. Factors including obesity, African ancestry and childhood are associated with increased asthma severity. Considering the high morbidity caused by asthma, relatively few classes of drugs exist to control this common disease. Therefore, new therapeutic strategies may be needed to reduce asthma's impact on public health. Data suggest that a high fat diet that is deficient in omega-3 fatty acids could promote both obesity and excessive inflammation, resulting in greater asthma severity. Small trials with supplemental omega-3 fatty acids have been conducted with encouraging but inconsistent results. The variability in response seen in past trials may be due to the past subjects' genetics (specifically ALOX5 rs59439148) or their particular asthma phenotypes. Therefore, the "Nutrigenetic response to Omega-3 Fatty acids in Obese Asthmatics (NOOA)" trial is currently underway and was designed as a randomized, double-blind, placebo controlled intervention study to determine if supplemental omega-3 fatty acids improves symptoms among obese adolescents and young adults with uncontrolled asthma. Here we report the design and rationale for the NOOA trial. Participants were given either 3.18 g daily of eicosapentaenoic acid and 822 mg daily docosahexaenoic acid, or matched control soy oil, for 24 weeks. Change in the asthma control questionnaire score was the primary outcome. Secondary outcomes included spirometry, impulse oscillometry, exacerbation rate, airway biomarkers, systemic inflammation, leukotriene biosynthesis and T-lymphocyte function. NOOA may lead to a new therapeutic treatment strategy and greater understanding of the mechanistic role of diet in the pathogenesis of asthma.

Allergic disease in infants up to 2 years of age in relation to plasma omega-3 fatty acids and maternal fish oil supplementation in pregnancy and lactation.

We have previously reported a protective effect of maternal omega-3 long-chain polyunsaturated fatty acids (ω-3 LCPUFA) supplementation in pregnancy and lactation on IgE-associated eczema and food allergy in the infant during the first year of life. Here we investigate whether the effects of the LCPUFA supplementation on IgE-associated diseases last up to 2 yr of age and assess the relationship between plasma proportions of ω-3 PUFAs and the frequency and severity of infant allergic disease. 145 pregnant women, at risk of having an allergic infant, were randomized to daily supplementation with 1.6 g eicosapentaenoic acid (EPA) and 1.1 g docosahexaenoic acid (DHA) or placebo starting in the 25th gestational week and continuing through 3.5 months of breastfeeding. Clinical examinations, skin prick tests and analysis of maternal and infant plasma phospholipid fatty acids and infant specific IgE were performed. No difference in the prevalence of allergic symptoms was found between the intervention groups. The cumulative incidence of IgE-associated disease was lower in the ω-3-supplemented group (6/54, 13%) compared with the placebo group (19/62, 30%, p=0.01). Higher maternal and infant proportions of DHA and EPA were associated with lower prevalence of IgE associated disease (p=0.01-0.05) in a dose-dependent manner. Higher maternal and infant proportions of DHA and EPA were found if the infants presented none, when compared with multiple allergic symptoms, (p<0.05) regardless of sensitization. In summary, the ω-3 supplementation offered no obvious preventive effect on the prevalence of clinical symptoms of allergic disease, but the decrease in cumulative incidence of IgE-associated disease seen during the first year still remained until 2 yr of age. Furthermore, high proportions of DHA and EPA in maternal and infant plasma phospholipids were associated with less IgE-associated disease and a reduced severity of the allergic phenotype.

n-3 Fatty acid supplementation and regular moderate exercise: differential effects of a combined intervention on neutrophil function.

CVD is associated with a cellular inflammatory/immune response. n-3 PUFA and moderate aerobic exercise independently alter cytokine production and leucocyte function. There is limited evidence for the combined effect of these treatments on immune function, particularly in patients with risk factors for CVD. We hypothesised that exercise would enhance the anti-inflammatory effects of n-3 PUFA. In a randomised, placebo-controlled study, fifty volunteers were allocated double-blind to consume either sunflower oil (6 g/d, placebo) or DHA-rich fish oil (6 g/d; about 2 g n-3 PUFA; 1.6 g DHA /d) for 12 weeks. Volunteers were further randomised to undertake regular exercise (walking 3 d/week for 45 min at 75 % of maximum heart rate) or maintain their usual physical activity for 12 weeks. Immune functions were assessed in blood taken initially and after 12 weeks. There was no effect on cytokine production by T cells and monocytes. Superoxide anion production from stimulated blood neutrophils was decreased by fish oil (19.5 (sem 8.5) %, P = 0.016) but not by exercise, and this change was negatively correlated with the incorporation of DHA into erythrocytes (r-0.385, P = 0.047). Participation in regular exercise maintained neutrophil bactericidal activity, which decreased in non-exercising subjects (2.9 (sem 0.7) %, P = 0.013). Neutrophil chemotaxis and adherence were not significantly affected by exercise, oil, or the combination of the two. Thus the combination of moderate exercise and fish-oil supplementation, which reduces cardiovascular risk, may also help to counteract inflammation.

Effects of fish oil in parenteral nutrition.

OBJECTIVE: Fish oil is a rich source of omega-3 fatty acids (FAs), especially eicosapentaenoic acid and docosahexaenoic acid. The existing data suggest that eicosapentaenoic acid and docosahexaenoic acid are the active agents in fish oil. A number of clinical trials have shown that dietary fish oil supplementation has antiatherogenic properties and immunomodulation effects. Fish oils are not used widely in parenteral nutrition because fish oil emulsions have not been commercially available until very recently. Studies concerning the use of fish oil in parenteral route are rare. METHODS: We reviewed the effect of parenteral fish oil infusion on lipid metabolism and immune response in normal and disease conditions. RESULTS: Studies showed that the main effects of parenteral infusion of fish oil are: 1) incorporation of omega-3 FAs into cellular membranes of many cell populations that consequently influence the disease process of some disease conditions, 2) an effect on eicosanoid metabolism leading to a decrease in platelet aggregation and thrombosis, 3) amelioration of the severity of diet-induced hepatic steatosis, 4) less accumulation of lipid peroxidation products in liver tissue, and 5) immunomodulation effects and therapeutic benefits in animal disease models or various disease conditions of humans. Most of these studies suggested that parenteral infusion of omega-3 FAs have clinical beneficial effects comparable to those of dietary administration. However, different effects of omega-3 and omega-6 FAs in some situations has been reported. For example, plasma triacylglycerol levels were not lowered after fish oil infusion in normal or diabetic rats when compared with those of safflower oil or soybean oil infusion. The reason for the difference remain unclear. CONCLUSION: The metabolic and immunologic effects of parenteral use of omega-3 FAs requires further evaluation, especially in some disease conditions.

n-3 polyunsaturated fatty acids inhibit the antigen-presenting function of human monocytes.

Diets rich in n-3 polyunsaturated fatty acids (PUFAs) are associated with suppression of cell-mediated immune responses, but the mechanisms are unclear. We hypothesized that n-3 PUFAs can inhibit the function of human antigen-presenting cells. A prerequisite for this role of blood monocytes is the cell surface expression of major histocompatibility complex (MHC) class II molecules [human leukocyte antigen (HLA)-DR, -DP, and -DQ], aided by the presence of intercellular adhesion molecule-1 (ICAM-1) and leukocyte function associated antigens 1 and 3. We showed previously that the n-3 PUFA eicosapentaenoic acid (EPA) inhibits the expression of HLA-DR on unstimulated human monocytes in vitro, but that docosahexaenoic acid (DHA) enhances its expression. However, both n-3 PUFAs suppress the expression of HLA-DR, HLA-DP, and ICAM-1 on interferon-gamma-activated monocytes. We also established that dietary fish-oil supplementation can inhibit the expression of these surface molecules on circulating human monocytes. We subsequently showed that when EPA and DHA were combined in the same ratio as is commonly found in fish-oil-supplement capsules (3:2), there was no significant effect in vitro on the expression of HLA-DR on unstimulated monocytes, but the expression on activated monocytes remained significantly inhibited. In the same in vitro system, the ability of activated monocytes to present antigen to autologous lymphocytes was significantly reduced after culture with the combined n-3 PUFAs. These findings provide one potential mechanism for the beneficial effect of fish oil in the treatment of rheumatoid arthritis, a disorder associated with elevated expression of MHC class II and adhesion molecules on monocytes present within affected joints.