12-hydroxy-5-8-10-14-eicosatetraenoic-acid and Hypersensitivity

Allergy has been associated with altered fatty acid and inflammatory status. In this cross-sectional study of 321 rural iron deficient (ID) South African children (aged 6-11 years), a subsample (n=111) of children with parent-reported allergy data were divided into an allergic (n=30) and non-allergic (n=81) group and compared. PBMC arachidonic acid (ARA; P=0.010) and the PBMC ARA to dihomo-gamma-linolenic acid (DGLA) ratio (P=0.035) were lower in the allergic children. Plasma 12-hydroxyeicosatetraenoic acid and 17-hydroxydocosahexaenoic acid (17-HDHA) were higher (P=0.040 and 0.020, respectively) in the allergic group. Thus, a fatty acid composition and lipid mediator levels indicative of increased release of ARA from PBMC membranes, increased inflammation as well as the resolving thereof, were associated with parent-reported allergy symptoms. This study used baseline data of an intervention study which was registered at clinicaltrials.gov as NCT01092377.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 8,11,14-Eicosatrienoic Acid; Anemia, Iron-Deficiency; Arachidonic Acid; Child; Cross-Sectional Studies; Docosahexaenoic Acids; Female; Humans; Hypersensitivity; Male; Rural Population; South Africa

We showed recently that IL-4 causes mitochondrial dysfunction in allergic asthma. IL-4 is also known to induce 12/15-lipoxygenase (12/15-LOX), a potent candidate molecule in asthma. Because vitamin E (Vit-E) reduces IL-4 and inhibits 12/15-LOX in vitro, here we tested the hypothesis that Vit-E may be effective in restoring key mitochondrial dysfunctions, thus alleviating asthma features in an experimental allergic murine model. Ovalbumin (OVA)-sensitized and challenged male BALB/c mice showed the characteristic features of asthma such as airway hyperresponsiveness (AHR), airway inflammation, and airway remodeling. In addition, these mice showed increase in the expression and metabolites of 12/15-LOX, reduction in the activity and expression of the third subunit of mitochondrial cytochrome-c oxidase, and increased cytochrome c in lung cytosol, which indicate that OVA sensitization and challenge causes mitochondrial dysfunction. Vit-E was administered orally to these mice, and 12/15-LOX expression, key mitochondrial functions, ultrastructural changes of mitochondria in bronchial epithelia, and asthmatic parameters were determined. Vit-E treatment reduced AHR, Th2 response including IL-4, IL-5, IL-13, and OVA-specific IgE, eotaxin, transforming growth factor-beta1, airway inflammation, expression and metabolites of 12/15-LOX in lung cytosol, lipid peroxidation, and nitric oxide metabolites in the lung, restored the activity and expression of the third subunit of cytochrome-c oxidase in lung mitochondria and bronchial epithelia, respectively, reduced the appearance of cytochrome c in lung cytosol, and also restored mitochondrial ultrastructural changes of bronchial epithelia. In summary, these findings show that Vit-E reduces key mitochondrial dysfunctions and alleviates asthmatic features.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Airway Remodeling; Animals; Anti-Asthmatic Agents; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cytochromes c; Disease Models, Animal; Electron Transport Complex IV; Goblet Cells; Hyperplasia; Hypersensitivity; Immunoglobulin E; Interleukin-13; Interleukin-4; Interleukin-5; Linoleic Acids; Lung; Male; Mice; Mice, Inbred BALB C; Mitochondria; Ovalbumin; Oxidative Stress; Pulmonary Fibrosis; Transforming Growth Factor beta1; Vitamin E

Amoxanox has potent antiallergic activity because it inhibits the release of chemical mediators such as histamine and leukotrienes. We studied the in vitro effect of amoxanox on arachidonic acid metabolism, including the lipoxygenase and cyclooxygenase pathways. Amoxanox inhibited calcium ionophore A23187-induced formation of 5-HETE, LTB4, SRS-A (LTC4, LTD4 and LTE4), and 12-HETE in rat peritoneal resident monocytes. These results indicate that amoxanox inhibits 5- and 12-lipoxygenases. The compound, however, did not affect the formation of TXB2 or 6-keto-PGF1 alpha in guinea pig lung fragments and PGE2 or PGF2 alpha in bovine seminal vesicles, suggesting that it did not inhibit cyclooxygenase. These results show that the antiallergic action of amoxanox is associated, at least in part, with the reduction of leukotrienes due to the inhibition of lipoxygenases.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 5,8,11,14-Eicosatetraynoic Acid; Aminopyridines; Animals; Asthma; Calcimycin; Cattle; Guinea Pigs; Histamine H1 Antagonists; Hydroxyeicosatetraenoic Acids; Hypersensitivity; In Vitro Techniques; Leukotriene B4; Lipoxygenase Inhibitors; Lung; Male; Monocytes; Prostaglandins; Rats; Rats, Inbred Strains; SRS-A; Thromboxane B2

Macrophages isolated from hypersensitivity (Schistosoma mansoni egg) and foreign body- (Sephadex bead) type granulomas were evaluated with regard to superoxide anion (O2-) production and arachidonic acid metabolism. Granuloma macrophages from schistosome-infected mice were examined during both the acute and modulated phases of the disease. In addition, the populations were characterized phenotypically by measurement of Ia antigen expression. Based on differences in the parameters studied at least three different macrophage populations could be identified in acute, modulated, and foreign body-type lesions, respectively. Macrophages from acute lesions (8-week granuloma macrophages) produced significant amounts of O2-, prostaglandins, and monohydroxyeicosatetraenoic acids without the addition of an exogenous stimulus. These cells also showed a high degree of Ia expression. In contrast, macrophages from modulated (20-week granuloma macrophages) and foreign body (foreign body granuloma macrophages) lesions required stimulation with phorbol ester to evoke significant O2- production and minimally metabolized arachidonic acid. However, 20-week and foreign body granuloma macrophages could be distinguished by their high and low degrees of Ia expression, respectively. The role of lymphokines and other intercellular signals in determining macrophage activation states within granulomas is discussed.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonic Acids; Cells, Cultured; Female; Foreign-Body Reaction; Granuloma; Histocompatibility Antigens Class II; Hypersensitivity; Macrophages; Mice; Mice, Inbred CBA; Prostaglandins; Schistosoma mansoni; Schistosomiasis; Superoxides