A combination of LCPUFA ameliorates airway inflammation in asthmatic mice by promoting pro-resolving effects and reducing adverse effects of EPA

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 EPAderived LTB 5 and LTC 5 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 LTB 5 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.

CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

“…DHA and EPA differentially modulate membrane fluidity, lipid oxidation, and signal transduction ( Sherratt and Mason, 2018 ) and are precursors of resolvins, bioactive lipids that control the resolution of inflammation. A combination of EPA and DHA can reduce induced inflammation in mouse models of asthma ( Fussbroich et al, 2020 ). Treatment of F508del CFTR mice with a diet enriched in ω-3 PUFA reduces lung disease ( Portal et al, 2018 ), however, a recent Cochrane meta-analysis of five limited trials did not indicate that ω-3 PUFA dietary supplementation is beneficial for CF patients ( Watson and Stackhouse, 2020 ).…”

A high docosahexaenoic acid diet alters lung inflammation and recovery following repetitive exposure to aqueous organic dust extracts

“…Omega-3 and omega-6 PUFAs are metabolized into different classes of bioactive lipids. There is accumulating evidence that DHA-derived active metabolites are in part responsible for their beneficial effects in suppressing airway inflammation [ 13 , 18 , 61 , 62 ]. DHA is mainly metabolized by cytochrome P450, COX and LOX enzymes, which generate many active eicosanoids including epoxides and prostaglandins, as well as specialized pro-resolving mediators (SPMs, leukotrienes, lipoxins, resolvins and maresins) [ 8 ].…”

Leukotriene B4 limits the effectiveness of fish oil in an animal model of asthma

“…These metabolites are produced by non-enzymatic oxidation of ARA and via the 15-LOX pathway, respectively. The reduction in the levels of these four eicosanoids is most likely related to the incorporation of the biologically active n-3 fatty acids present in fish oil: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are incorporated into inflammatory cell membranes decreasing the relative content of ARA [ 47 , 48 ]. We previously reported that fish oil supplementation results in increased EPA and DHA and decreased ARA in lung tissue from these rats [ 49 ].…”