Fish oil is rich in the polyunsaturated N-3 fatty acids, eicosapentaenoic (EPA) and docosahexaenoic acids (DCHA). EPA competes with arachidonic acid (AA) for metabolism by the cyclooxygenase and lipoxygenase pathways. Selective metabolites derived from EPA have reduced biological activities as compared with the AA-derived counterparts. Dietary supplementation with EPA led to incorporation of EPA into membrane phospholipids, an inhibition of 5-lipoxygenase pathway activity, and a reduction of the elaboration of platelet-activating factor. Neutrophil chemotaxis and the capacity of these cells to adhere to endothelial cells are substantially attenuated. This suggests that EPA has anti-inflammatory potential. Clinical trials in rheumatoid arthritis, psoriasis, atopic dermatitis, and bronchial asthma have shown beneficial effects. Whether the benefit obtained clinically is sufficient to replace or significantly reduce any clinical condition remains to be answered.

1. Lipoxin A4 (LXA4) and lipoxin B4 (LXB4) have been evaluated for their capacities to modulate neutrophil (PMN) migration and endothelial cell adherence using compounds prepared by total chemical synthesis. 2. Increased PMN migration was seen with concentrations of LXA4 from 10−9 mol/l to 10−7 mol/l. LXA4 was 100-fold less potent than leukotriene B4 (LTB4) and it elicited only one-half of the maximal response of LTB4. 3. The (5S,6S,15S)-isomer of LXA4 induced only a weak migratory response and LXB4 was inactive, suggesting that the activity of LXA4 was stereospecific. 4. Modified chequerboard analysis indicated that LXA4 was a chemokinetic agent. 5. Preincubation of PMN with increasing concentrations of LXA4 induced a very similar dose- and time-dependent inhibition of the subsequent response to 10−7 mol/l LTB4 or 10−7 mol/l N-formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP). The inhibition was observed at 10−10 mol/l LXA4; the concentration which produced 50% inhibition was 10−8 mol/l and 100% inhibition of PMN locomotion occurred at 10−6 mol/l LXA4. 6. The (5S,6S,15S)-isomers of LXA4 and LXB4 were 5- and 100-fold less potent than LXA4, respectively, in suppressing LTB4- or FMLP-induced PMN migration. 7. Preincubation of PMN with LXA4 led to a suppression of calcium mobilization, as assessed by Quin2-AM fluorescence, when the cells were subsequently stimulated under optimal conditions by LTB4 or FMLP. 8. These results suggest that the inhibitory activity of lipoxins may be related to the capacity of these molecules to regulate calcium ion mobilization. 9. LXA4 and LXB4 did not promote PMN adherence to human endothelial cell monolayers and they did not modulate FMLP-stimulated PMN-endothelial cell adhesion.

The effects of dietary supplementation with fish oil lipids on the airways responses to allergen and neutrophil biochemistry and function have been studied in 17 atopic asthmatic subjects. Nine subjects received 18 capsules of Max-EPA (3.2 g eicosapentaenoic acid and 2.2 g docosahexaenoic acid) a day and eight subjects received identical capsules containing olive oil, for 10 wk in a double-blind fashion. There were no differences between prediet values and those observed after dietary supplementation with Max-EPA or placebo in the dose of allergen causing an acute asthmatic response as assessed by a 35% fall in specific airways conductance (PD35), the extinction dose of allergen on skin prick testing, the histamine PD35, or the total serum IgE concentrations. Twelve of the 17 subjects developed late asthmatic responses after allergen challenge prediet. Six of these subjects received Max-EPA, and six received placebo capsules. As compared to prediet values, the magnitude of the allergen-induced late asthmatic response was significantly attenuated from 2 to 7 h after allergen challenge following dietary supplementation with Max-EPA (p less than 0.005) but not with placebo. The attenuation of the late response was not accompanied by any significant change in the clinical severity of disease as assessed by diurnal peak expiratory flow rates, symptom scores, or bronchodilator drug usage.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

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.

1. Leukotriene (LT) B3 was prepared by total chemical synthesis and its identity was confirmed by nuclear magnetic resonance analysis and proton homonuclear plot of connectivities and chemical shift assignments. The effects of LTB3 on complement receptor enhancement, chemotaxis and lysozyme release in human neutrophils (PMN) were compared with those of LTB4 and LTB5. 2. LTB3 and LTB4 elicited a virtually identical dose- and time-dependent enhancement in complement receptors type 1 (CR1) and type 3 (CR3) and release of lysozyme. LTB5 was approximately 100 times less potent than LTB4 in enhancing CR1 and CR3, whereas it was 10,000 times less potent than LTB4 in releasing lysozyme from human PMN. 3. LTB3 and LTB5 were respectively 5- and 100-fold less potent than LTB4 in eliciting chemotaxis. 4. These findings indicate that the pro-inflammatory potential of LTB3 and LTB4 are similar, whereas LTB5 is substantially less potent as an inflammatory mediator. 5. The finding that LTB5 is a weak and partial agonist relative to LTB3 and LTB4 could be due to the rigidity of the C-17-C-18 double bond in LTB5. This may interfere with the active site specificity of LTB5 to a substantial extent. 6. One approach to the development of antagonists to the LTB4 receptor may be to establish a rigid structure in the C-17-C-18 region of the LTB4 molecule.