Original articleEicosapentaenoic acid is more effective than docosahexaenoic acid in inhibiting proinflammatory mediator production and transcription from LPS-induced human asthmatic alveolar macrophage cells
Introduction
Over the past three decades there has been significant interest in the therapeutic potential of fish oils for various inflammatory conditions such as rheumatoid arthritis, inflammatory bowel diseases, and asthma. Fish oil, rich in omega-3 (n-3) polyunsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), appears to have additional antiphlogistic properties primarily through their effects on the neutrophil and macrophage (Mφ) component of the inflammatory response.1, 2, 3, 4, 5, 6, 7
Eicosapentaenoic acid can compete with arachidonic acid (AA), as a substrate for cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO) enzymes and be converted to less inflammatory eicosanoids.6, 8 At present the mechanism(s) underpinning the anti-inflammatory effects of DHA are unclear, but may be related to altered gene transcription and translation via direct or indirect actions on intracellular signaling pathways.9, 10, 11 In addition, n-3 PUFA-derived mediators such as lipoxin, docosatrienes resolvins and neuroprotectins may also have anti-inflammatory, pro-resolving and protective properties.12
The observational evidence on fish oil effects has been relatively consistent in demonstrating protection against asthma and/or allergy in relation to a high intake, and ecological and other cross-sectional data support the hypothesis that n-6 PUFA may increase and n-3 PUFA may decrease asthma risk.13 While the clinical data on the effect of fish oil supplementation in asthma has been equivocal14 supplementing the diet with fish oil in individuals with exercise-induced asthma (EIA) has yielded promising results.15, 16 Our laboratory has shown that 3 weeks of fish oil supplementation reduced the severity of EIA, airway inflammation and bronchodilator use, and improved asthma symptom scores in elite athletes15 and asthmatic individuals.16
The majority of studies investigating the effects of n-3 PUFA on asthma/EIA have either employed fish oils rich in EPA or oils which contain a heterogeneous blend of EPA and DHA. Only a few studies have examined the effects of supplementing asthmatic patients with pure EPA and/or DHA, with conflicting results.14 Data are therefore insufficient to make recommendations for intake of specific n-3 PUFA in asthma, e.g. EPA vs. DHA vs. EPA + DHA combined.17 Although many studies have investigated the effects of EPA and DHA on macrophage function in animal models and cell lines, there is little evidence about the effects of these lipids on primary human macrophages obtained from asthmatic patients.
Therefore, the main aim of this study was to compare the individual effects of EPA and DHA, and a variety of heterogeneous blends of EPA and DHA, on eicosanoid and cytokine generation from LPS-stimulated human asthmatic alveolar macrophages (AMφ). In addition, the effects of EPA and DHA on cytokine mRNA expression were investigated in the LPS-stimulated AMφ.
Section snippets
Methods
Twenty non-smoking adults with asthma were recruited to this study. Asthma was diagnosed by a history of recurrent wheezing and chest tightness and a previous physician diagnosis. All subjects had clinically treated mild-to-moderate persistent asthma, with an FEV1 greater than 70% of predicted.18 Inhaled corticosteroids, 5-lipoxygenase inhibitors and leukotriene receptor antagonists were withheld for 4 weeks prior to fiberoptic bronchoscopy. Subjects were also excluded if they had a history of
Results
The fluid recovered, total cell count and percent differential airway cell counts recovered from bronchial samples are presented in Table 1. The unstimulated AMφ cells did not demonstrate any significant differences (p > 0.05) in LTB4, PGD2, TNF-α or IL-1β production among the high dose (120 μM) treatment groups (Fig. 1, panel A–D). DMEM pretreated controls demonstrated a significant increase (p < 0.05) in LTB4, PGD2, TNF-α and IL-1β production in response to LPS stimulation (Fig. 1, panel A–D). The
Discussion
This study has demonstrated for the first time that pure EPA media reduced TNF-α and IL-1β mRNA expression and the production of LTB4, PGD2 and TNF-α and IL-1β from LPS-stimulated primary AMφ cells obtained from asthmatic patients to a much greater extent than pure DHA. Interestingly, the EPA-rich media (EPAX 4510) significantly reduced cytokine mRNA expression and generation of eicosanoids and cytokines from LPS-stimulated AMφ cells to a much greater degree than both the pure DHA and the
Conflict of interest
The authors report no conflict of interest.
Acknowledgments
The authors would like to thank the participating asthmatic adults for volunteering to this study.
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