8-11-14-eicosatrienoic-acid and Asthma

Airway remodeling in asthma is difficult to treat because of its complex pathophysiology that involves proinflammatory cytokines, as well as the arachidonic acid cytochrome P-450 (CYP) pathway; however, it has received little attention. In this study, we assessed the efficacy of a soluble epoxide hydrolase (sEH) on airway remodeling in a mouse model of chronic asthma. The expression of sEH and CYP2J2 and the level of 14,15-epoxyeicosatrienoic acid (14,15-EET), airway remodeling and hyperresponsiveness (AHR) were analyzed to determine the level of sEH inhibition. AUDA, a sEH inhibitor, was given daily for 9 weeks orally, which significantly increased the level of 14,15-EET by inhibiting the expression of sEH and increasing the expression of CYP2J2 in lung tissues. The inhibition of sEH reduced the expression of remodeling-related molecular markers, such as interleukin (IL)-13, IL-17, matrix metalloproteinase 9, N-cadherin, α-smooth muscle actin (α-SMA), S100A4, Twist, epithelial goblet cell metaplasia, and collagen deposition in bronchoalveolar lavage fluid (BAL fluid) and lung tissues. Moreover, remodeling-related eosinophil accumulation in the BAL fluid and infiltration into the lung tissue were improved by AUDA. Finally, AUDA alleviated AHR, which is a functional indicator of airway remodeling. The effect of AUDA on airway remodeling was related to the downregulation of extracellular-regulated protein kinases (Erk1/2), c-Jun N-terminal kinases (JNK) and signal transducer and activator of transcription 3 (STAT3). To our knowledge, this is the first report to demonstrate that inhibition of sEH exerts significant protective effects on airway remodeling in asthma.

Topics: 8,11,14-Eicosatrienoic Acid; Adamantane; Airway Remodeling; Animals; Asthma; Bronchoalveolar Lavage Fluid; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Disease Models, Animal; Epoxide Hydrolases; Female; Humans; Lauric Acids; Lung; MAP Kinase Signaling System; Mice; Ovalbumin; Signal Transduction; STAT3 Transcription Factor

Dietary supplementation with botanical oils that contain n-6 and n-3 eighteen carbon chain (18C)-PUFA such as γ linolenic acid (GLA, 18:3n-6), stearidonic acid (SDA, 18:4n-3) and α linolenic acid (ALA, 18:3n-3) have been shown to impact PUFA metabolism, alter inflammatory processes including arachidonic acid (AA) metabolism and improve inflammatory disorders.. The diet of mild asthmatics patients was supplemented for three weeks with varying doses of two botanical seed oils (borage oil [Borago officinalis, BO] and echium seed oil [Echium plantagineum; EO]) that contain SDA, ALA and GLA. A three week wash out period followed. The impact of these dietary manipulations was evaluated for several biochemical endpoints, including in vivo PUFA metabolism and ex vivo leukotriene generation from stimulated leukocytes.. Supplementation with several EO/BO combinations increased circulating 20-22 carbon (20-22C) PUFAs, including eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and dihommo-gammalinolenic acid (DGLA), which have been shown to inhibit AA metabolism and inflammation without impacting circulating AA levels. BO/EO combinations also inhibited ex vivo leukotriene generation with some combinations attenuating cysteinyl leukotriene generation in stimulated basophils by >50% and in stimulated neutrophils by >35%.. This study shows that dietary supplementation with BO/EO alters 20-22C PUFA levels and attenuates leukotriene production in a manner consistent with a reduction in inflammation.

Topics: 8,11,14-Eicosatrienoic Acid; Adolescent; Adult; alpha-Linolenic Acid; Asthma; Cells, Cultured; Dietary Supplements; Echium; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; gamma-Linolenic Acid; Humans; Inflammation; Leukocytes, Mononuclear; Leukotrienes; Male; Middle Aged; Plant Oils; Seeds

Fullerenes are molecules being investigated for a wide range of therapeutic applications. We have shown previously that certain fullerene derivatives (FDs) inhibit mast cell (MC) function in vitro, and here we examine their in vivo therapeutic effect on asthma, a disease in which MCs play a predominant role.. We sought to determine whether an efficient MC-stabilizing FD (C(70)-tetraglycolate [TGA]) can inhibit asthma pathogenesis in vivo and to examine its in vivo mechanism of action.. Asthma was induced in mice, and animals were treated intranasally with TGA either simultaneously with treatment or after induction of pathogenesis. The efficacy of TGA was determined through the measurement of airway inflammation, bronchoconstriction, serum IgE levels, and bronchoalveolar lavage fluid cytokine and eicosanoid levels.. We found that TGA-treated mice have significantly reduced airway inflammation, eosinophilia, and bronchoconstriction. The TGA treatments are effective, even when given after disease is established. Moreover, we report a novel inhibitory mechanism because TGA stimulates the production of an anti-inflammatory P-450 eicosanoid metabolites (cis-epoxyeicosatrienoic acids [EETs]) in the lung. Inhibitors of these anti-inflammatory EETs reversed TGA inhibition. In human lung MCs incubated with TGA, there was a significant upregulation of CYP1B gene expression, and TGA also reduced IgE production from B cells. Lastly, MCs incubated with EET and challenged through FcεRI had a significant blunting of mediator release compared with nontreated cells.. The inhibitory capabilities of TGA reported here suggest that FDs might be used a platform for developing treatments for asthma.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Asthma; Bronchoconstriction; Eosinophilia; Female; Fullerenes; Immunoglobulin E; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL

It has been suggested that atopic dermatitis (AD) is associated with impaired delta-6 desaturase activity and the subsequent altered composition of n-6 essential fatty acids (EFAs).. To investigate whether n-6 EFA deficiency accounts for AD by affecting transepidermal water loss or the immune response.. Serum levels of n-6 EFAs were measured using gas chromatography-mass spectrometry in a well-defined group of 35 children with AD (IgE level >150 U/mL); 35 age-matched children with allergic rhinitis, asthma, or both (IgE level >150 U/mL); and 31 nonatopic controls (IgE level <100 U/mL). Skin barrier function was evaluated by measuring transepidermal water loss and severity of AD by computing the Scoring Atopic Dermatitis (SCORAD) index.. Atopic children had higher levels of linoleic acid (LA) and lower levels of its metabolites. Furthermore, gamma-linolenic acid to LA and dihommo-gamma-linolenic acid to LA ratios were significantly reduced in atopic patients. Transepidermal water loss and the SCORAD index were negatively correlated with serum levels of LA metabolites. There was no correlation between the SCORAD index and IgE level (P = .51) or between n-6 EFA concentrations and IgE level (P > .10).. Deficits in n-6 EFAs were correlated with the severity of AD by affecting skin barrier function and cutaneous inflammation. The link between impaired n-6 EFA metabolism and IgE level could not be defined.

Topics: 8,11,14-Eicosatrienoic Acid; Adolescent; Arachidonic Acid; Asthma; Child; Child, Preschool; Dermatitis, Atopic; Epidermis; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Female; gamma-Linolenic Acid; Humans; Immunoglobulin E; Linoleic Acid; Lipids; Male; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Water; Water Loss, Insensible

It has been suggested that atopy is associated with an impairment in the delta 6-desaturation of (n-6)-polyunsaturated fatty acids and subsequently low levels of eicosanoid precursors. To evaluate this hypothesis we analyzed the fatty acid composition of plasma phospholipids and plasma cholesterol esters in a well-defined group of children with atopic bronchial asthma (n = 17) and age-matched healthy controls (n = 10). Atopic children showed significantly higher levels of linoleic acid and lower proportions of arachidonic acid in plasma lipids. No differences were observed with respect to gamma-linolenic acid (GLA) and dihomo-gamma-linolenic acid (DHLA). It is concluded that there is no biochemical evidence for a delta 6-desaturation defect in atopic children and therefore no justification for the supplementation of GLA and DHLA; e.g., by the use of evening primrose oil preparations.

Topics: 8,11,14-Eicosatrienoic Acid; Asthma; Child; Cholesterol Esters; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Female; gamma-Linolenic Acid; Humans; Hypersensitivity, Immediate; Lipids; Male; Phospholipids

It has been demonstrated that patients with atopic disease have anomalies of fatty acid composition, as a result of altered metabolism or abnormal incorporation of fatty acids into the tissues. In the present study, in 57 newborns 'at risk' for atopic disease, the polyunsaturated fatty acid (PUFA) levels were found to be lower in cord blood in infants who subsequently developed atopic disease than in non-atopics. In all babies, levels of arachidonic acid and dihomo-gamma-linolenic acid in sera at 1 and 3 months of age were lower than those in cord blood. These changes were more marked in children who subsequently developed atopic disease, and in those who, independently of signs and/or symptoms of atopic disease, were formula-fed. A comparison between IgE and PUFA levels revealed no significant differences at any tested time interval. In conclusion, our data suggest that in children 'at risk' for atopy, PUFA levels may be predictive of atopic disease.

Topics: 8,11,14-Eicosatrienoic Acid; Arachidonic Acid; Asthma; Biomarkers; Breast Feeding; Dermatitis, Atopic; Fatty Acids, Unsaturated; Female; Fetal Blood; Follow-Up Studies; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Infant, Newborn; Male; Neonatal Screening

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Asthma; Chromones; Dogs; Fatty Acids, Unsaturated; Guinea Pigs; Rats; Receptors, Leukotriene; Receptors, Prostaglandin; SRS-A