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n−3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases

Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid, production of inflammatory cytokines and T cell reactivity. In parallel, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DHA give rise to anti-inflammatory and inflammation resolving resolvins and protectins. Mechanisms underlying the anti-inflammatory actions of n-3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes, activation of the anti-inflammatory transcription factor NR1C3 (i.e. peroxisome proliferator activated receptor ?) and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked. In adult humans, an EPA plus DHA intake greater than 2?g?day(-1) seems to be required to elicit anti-inflammatory actions, but few dose finding studies have been performed. Animal models demonstrate benefit from n-3 fatty acids in rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma. Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta-analyses of the data. Clinical trails of fish oil in patients with IBD and asthma are inconsistent with no overall clear evidence of efficacy.

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Omega‐3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology?

Consumption of n-6 polyunsaturated fatty acids greatly exceeds that of n-3 polyunsaturated fatty acids. The n-6 polyunsaturated fatty acid arachidonic gives rise to the eicosanoid family of inflammatory mediators (prostaglandins, leukotrienes and related metabolites) and through these regulates the activities of inflammatory cells, the production of cytokines and the various balances within the immune system. Fish oil and oily fish are good sources of long chain n-3 polyunsaturated fatty acids. Consumption of these fatty acids decreases the amount of arachidonic acid in cell membranes and so available for eicosanoid production. Thus, n-3 polyunsaturated fatty acids act as arachidonic acid antagonists. Components of both natural and acquired immunity, including the production of key inflammatory cytokines, can be affected by n-3 polyunsaturated fatty acids. Although some of the effects of n-3 fatty acids may be brought about by modulation of the amount and types of eicosanoids made, it is possible that these fatty acids might elicit some of their effects by eicosanoid-independent mechanisms. Such n-3 fatty acid-induced effects may be of use as a therapy for acute and chronic inflammation, and for disorders which involve an inappropriately activated immune response.

Polyunsaturated fatty acids, inflammation and immunity

The fatty acid composition of inflammatory and immune cells is sensitive to change according to the fatty acid composition of the diet. In particular, the proportion of different types of polyunsaturated fatty acids (PUFA) in these cells is readily changed, and this provides a link between dietary PUFA intake, inflammation, and immunity. The n-6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds, which have important roles in inflammation and in the regulation of immunity. Fish oil contains the n-3 PUFA eicosapentaenoic acid (EPA). Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators. In addition, EPA is a substrate for cyclooxygenase and lipoxygenase and gives rise to mediators that often have different biological actions or potencies than those formed from AA. Animal studies have shown that dietary fish oil results in altered lymphocyte function and in suppressed production of proinflammatory cytokines by macrophages. Supplementation of the diet of healthy human volunteers with fish oil-derived n-3 PUFA results in decreased monocyte and neutrophil chemotaxis and decreased production of proinflammatory cytokines. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease. Clinical studies have reported that fish oil supplementation has beneficial effects in rheumatoid arthritis, inflammatory bowel disease, and among some asthmatics, supporting the idea that the n-3 PUFA in fish oil are anti-inflammatory and immunomodulatory.

Polyunsaturated fatty acids, inflammation, and immunity.

Recruitment of inflammatory leucocytes to the airways may play a part in the pathogenesis of asthma. As dietary enrichment with fish oil lipids can suppress leucocyte function, the effect of these lipids on asthma control and neutrophil function was studied in 20 subjects with mild asthma. Twelve subjects received capsules containing 3.2 g of eicosapentaenoic acid and 2.2 g of docosahexaenoic acid daily and eight subjects received placebo capsules containing olive oil for 10 weeks in a double blind fashion. Baseline specific airways conductance, airways responsiveness to histamine and exercise, diurnal peak expiratory flow, symptom scores, and bronchodilator use were measured. Neutrophil fatty acid composition was evaluated by gas chromatography, calcium ionophore induced neutrophil leukotriene (LT)B4 and LTB5 generation were measured by reverse phase high performance liquid chromatography and radioimmunoassay, and neutrophil chemotactic responses to formyl-methionyl-leucyl-phenylalanine (FMLP) and LTB4 were assessed by a microchemotaxis technique. Although the fish oil supplemented diet produced a greater than 10 fold increase in the eicosapentaenoic acid content of neutrophil phospholipids, there was no significant change in airways responsiveness to histamine or any change in any of the clinical measurements. After dietary supplementation with fish oil there was a 50% inhibition of total LTB (LTB4 + LTB5) generation by ionophore stimulated neutrophils and neutrophil chemotaxis was substantially suppressed. Neutrophil function remained unchanged in the placebo group. It is concluded that in subjects with mild asthma a fish oil enriched diet attenuates neutrophil function without changing the severity of asthma.

https://thorax.bmj.com/content/thoraxjnl/43/2/84.full.pdf

Effect of dietary supplementation with fish oil lipids on mild asthma.

Serum neutrophil chemotactic activity (NCA) and plasma histamine concentrations were measured in 9 asthmatic subjects with exercise-induced asthma after inhalation challenge with ultrasonically nebulized 3.6% hypertonic saline, which was administered either in a dose-dependent manner (HSDR) or as a continuous single dose (HSC), and after cycle ergometer exercise. The mean decreases in FEV1 elicited by HSDR, HSC, and exercise were 26, 27, and 25%, respectively, and were not significantly different. There was an approximate 300% maximal increase in NCA detected after both HSC and exercise challenges. Gel filtration chromatography on columns of Ultragel ACA 34 indicated that the NCA released after HSC provocation and exercise were 600 to 700 kDa. There was an approximate 100% maximal increase in NCA after HSDR challenge, and this was significantly less (p = 0.016) than that after HSC and exercise. Exercise but not hypertonic challenge was associated with a basophilia and a significant increase in plasma histamine. There was a significant increase in plasma norepinephrine concentrations after exercise but not after HSC challenge in 7 asthmatics. Epinephrine concentrations did not change after exercise or HSC inhalation. NCA was measured in 5 subjects subjected to 2 HSC challenges that were separated by 60 min. There was an increase in NCA detected after both provocations. The increase after the second challenge was significantly greater (p = 0.27 x 10(-4)) than that observed after the initial provocation, despite a substantially reduced bronchoconstrictor response after the second challenge.

A comparison of mediator and catecholamine release between exercise- and hypertonic saline-induced asthma.

The generation of LTB4 by peripheral blood neutrophils (PMN) isolated before and for as long as 6 h after exercise-induced asthma (EIA) has been analyzed. Three and 6 h after the development of EIA, PMN isolated from 10 asthmatic subjects and stimulated in vitro by 2 x 10(8) and 4 x 10(8) zymosan particles per 2 x 10(6) PMN demonstrated a 12- and 4-fold enhancement, respectively, in the production of immunoreactive LTB4 as compared with PMN isolated before exercise. At 6 h after EIA, there was a redistribution of generated LTB4 such that 30 to 40% of LTB4 produced by zymosan-activated PMN was released extracellularly as compared with 10% before exercise. There was no significant enhancement in the generation of LTB4 by unstimulated PMN at any time point after exercise. Resolution by reverse-phase high performance liquid chromatography (HPLC) of products from [3H]arachidonic-acid-labeled and zymosan-activated PMN demonstrated that, in addition to LTB4, there was enhanced metabolism to 6-trans-LTB4, omega-oxidation metabolites of LTB4 and 5-HETE. Stimulation of PMN with 10 microM A23187 revealed a 2-, 6-, and 5-fold enhancement in the production of LTB4, 6-trans-LTB4, and 5-HETE, respectively, at 6 h after EIA, as measured by integrated ultraviolet absorbance after HPLC. There was no significant enhancement in LTB4 generation by PMN in 6 asthmatic subjects after methacholine-induced bronchospasm, and after exercise in 6 subjects who did not develop asthma. The augmentation of PMN LTB4 generation in EIA correlated with the extent of the early decrease in SGaw.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced generation of leukotriene B4 by neutrophils stimulated by unopsonized zymosan and by calcium ionophore after exercise-induced asthma.

Recruitment ofinflammatory leucocytes to theairways may playa partinthe pathogenesis ofasthma. Asdietary enrichment with fish oil lipids can suppressleucocyte function, the effect ofthese lipids onasthma control andneutrophil function was studied in20subjects withmild asthma. Twelve subjects received capsules containing 3-2g ofeicosapentaenoic acidand2-2g of docosahexaenoic acid daily andeight subjects received placebo capsules containing olive oilfor10 weeks inadouble blind fashion. Baseline specific airways conductance, airways responsiveness to histamine andexercise, diurnal peakexpiratory flow, symptomscores,andbronchodilator use were measured. Neutrophil fatty acidcomposition was evaluated bygas chromatography, calcium ionophore induced neutrophil leukotriene (LT)B4 andLTB5generation were measured byreverse phase high performance liquid chromatography andradioimmunoassay, andneutrophil chemotactic responsestoformyl-methionyl-leucyl-phenylalanine (FMLP)andLTB4were assessed bya micro- chemotaxis technique. Although thefish oilsupplemented diet produced a greater than10fold increase intheeicosapentaenoic acid content ofneutrophil phospholipids, there was no significant change inairways responsiveness tohistamine or any change inany oftheclinical measurements. After dietary supplementation withfish oil there was a50%inhibition oftotal LTB(LTB4+ LTB5) generation byionophore stimulated neutrophils andneutrophil chemotaxis was substantially suppressed. Neutrophil function remained unchanged intheplacebo group.Itisconcluded that in subjects with mildasthma afish oil enriched diet attenuates neutrophil function without changing the severity ofasthma. Asthmaischaracterised byairways inflammation, by bronchial hyperresponsiveness tonon-specific stimuli, andbyepisodic andreversible airflow obstruction. Studies bothinexperimental animals andinman have indicated an association betweenairways hyper- responsiveness andbronchial inflammation.'-' Ithas beensuggested thatairway inflammation may be central tothepathophysiology ofbronchial asthma. Eicosapentaenoic acidanddocosahexaenoic acid arepolyunsaturated fatty acids derived fromfish oil. Theyaretermed omega-3(C43) or N-3fatty acids because thefirst double bondinthemolecule isthree carbons removed fromtheterminal methyl group. Thesefatty acids competitively inhibit theformation Address forreprint requests: DrTakH Lee, Department ofMedicine, Guy'sHospital, LondonSEI9RT.

Frank House

Papers

Effect of dietary supplementation with fish oil lipids on mild asthma.

A comparison of mediator and catecholamine release between exercise- and hypertonic saline-induced asthma.

Enhanced generation of leukotriene B4 by neutrophils stimulated by unopsonized zymosan and by calcium ionophore after exercise-induced asthma.

Effect ofdietary supplementation withfish oillipids on mildasthma