Abstract
Lipid mediators derived from omega (n)-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFA) play key roles in bronchoconstriction, airway inflammation, and resolution processes in asthma. This study compared the effects of dietary supplementation with either a combination of LCPUFAs or eicosapentaenoic acid (EPA) alone to investigate whether the combination has superior beneficial effects on the outcome of asthmatic mice. Mice were sensitized with house dust mite (HDM) extract, and subsequently supplemented with either a combination of LCPUFAs or EPA alone in a recall asthma model. After the final HDM and LCPUFA administration, airway hyperresponsiveness (AHR), bronchoalveolar lavages, and lung histochemistry were examined. Lipid mediator profiles were determined by liquid chromatography coupled with tandem mass spectrometry (LC–MS–MS). The LCPUFA combination reduced AHR, eosinophilic inflammation, and inflammatory cytokines (IL-5, IFN-γ, and IL-6) in asthmatic mice, whereas EPA enhanced inflammation. The combination of LCPUFAs was more potent in downregulating EPA-derived LTB5 and LTC5 and in supporting DHA-derived RvD1 and RvD4 (2.22-fold and 2.58-fold higher levels) than EPA alone. Ex vivo experiments showed that LTB5 contributes to granulocytes’ migration and M1-polarization in monocytes. Consequently, the LCPUFA combination ameliorated airway inflammation by inhibiting adverse effects of EPA and promoting pro-resolving effects supporting the lipid mediator-dependent resolution program.
Highlights
IntroductionCharacterized by chronic respiratory eosinophilic inflammation, airway hyperresponsiveness (AHR), and remodeling of airways, asthma is a chronic disease affecting 300 million people worldwide.[1,2] In recent years, lipid mediators have been shown to play an essential role in inflammatory processes in asthma.[3,4] Pro-inflammatory lipid mediators, such as prostaglandins, leukotrienes, and thromboxanes induce bronchoconstriction and leukocyte infiltration, whereas specialized pro-resolving mediators (SPMs) downregulate infiltration, cytokine, and chemokine production and induce catabasis.[3,5,6] Lipid mediators derive from omega (n-)[3] and n-6 long-chain polyunsaturated fatty acids (LCPUFA), such as eicosapentaenoic (EPA), docosapentaenoic
A combination of long-chain polyunsaturated fatty acids (LCPUFA) but not eicosapentaenoic acid (EPA) alone ameliorates airway hyperresponsiveness in mice sensitized to house dust mite After mice were sensitized with HDM or PBS as a control for 10 consecutive days, they either received no supplementation, a combination of LCPUFAs, or single EPA supplementation for 24 days (Fig. 1a)
The respiratory resistance was even increased at 50 mg/mL compared with non-supplemented asthmatic mice (HDM: 3.97 ± 0.57 cmH2O × s/mL; EPA: 5.45 ± 1.22 cmH2O × s/mL (p < 0.05))
Summary
Characterized by chronic respiratory eosinophilic inflammation, airway hyperresponsiveness (AHR), and remodeling of airways, asthma is a chronic disease affecting 300 million people worldwide.[1,2] In recent years, lipid mediators have been shown to play an essential role in inflammatory processes in asthma.[3,4] Pro-inflammatory lipid mediators, such as prostaglandins, leukotrienes, and thromboxanes induce bronchoconstriction and leukocyte infiltration, whereas specialized pro-resolving mediators (SPMs) downregulate infiltration, cytokine, and chemokine production and induce catabasis.[3,5,6] Lipid mediators derive from omega (n-)[3] and n-6 long-chain polyunsaturated fatty acids (LCPUFA), such as eicosapentaenoic (EPA), docosapentaenoic DPA), docosahexaenoic (DHA), and arachidonic acid (AA). Several pro-resolving effects (e.g., the decrease of AHR and airway eosinophilia) are described for SPMs, such as RvE1, RvD1, PD1, LXA4 in asthma.[7,8,9,10]
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