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

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonic Acid; Asthma; Biological Transport; Cell Communication; Humans; Hydroxyeicosatetraenoic Acids; Inflammation Mediators; Kidney; Leukotrienes; Lipoxins; Lipoxygenase; Stereoisomerism

The mechanisms underlying asthmatic airway epithelial injury are not clear. 12/15-lipoxygenase (an ortholog of human 15-LOX-1), which is induced by IL-13, is associated with mitochondrial degradation in reticulocytes at physiological conditions. In this study, we showed that 12/15-LOX expressed in nonepithelial cells caused epithelial injury in asthma pathogenesis. While 12/15-LOX overexpression or IL-13 administration to naïve mice showed airway epithelial injury, 12/15-LOX knockout/knockdown in allergic mice reduced airway epithelial injury. The constitutive expression of 15-LOX-1 in bronchial epithelia of normal human lungs further indicated that epithelial 15-LOX-1 may not cause epithelial injury. 12/15-LOX expression is increased in various inflammatory cells in allergic mice. Though non-epithelial cells such as macrophages or fibroblasts released 12/15-LOX metabolites upon IL-13 induction, bronchial epithelia didn't release. Further 12-S-HETE, arachidonic acid metabolite of 12/15-LOX leads to epithelial injury. These findings suggested 12/15-LOX expressed in non-epithelial cells such as macrophages and fibroblasts leads to bronchial epithelial injury.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 3T3 Cells; Animals; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Asthma; Blotting, Western; Cell Line; Cytochromes c; Epithelium; Fibroblasts; Humans; Immunohistochemistry; Interleukin-13; Lactones; Linoleic Acids; Lung; Macrophages; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Mitochondria; Sesquiterpenes, Eudesmane

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

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Asthma; Biomarkers; Blood Chemical Analysis; Case-Control Studies; Chromatography, High Pressure Liquid; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Inflammation Mediators; Reference Standards; Rhinitis, Allergic, Seasonal

Aspirin (ASA)-induced asthma is a distinct clinical syndrome in which bronchoconstrictive response to nonsteroidal anti-inflammatory drugs can be predicted on the basis of their in vitro activity as inhibitors of cyclooxygenase. In ten ASA-sensitive asthmatics and ten matched healthy controls we measured 12-hydroxy-eicosatetraenoic acid (12-HETE) production by platelets and 5-hydroxy-eicosatetraenoic acid (5-HETE) and leukotriene B4 (LTB4) production by polymorphonuclear leucocytes. The blood cells were obtained before administration of the threshold doses of ASA and during the ASA-induced reactions. Initial levels of eicosanoids determined did not differ between the two groups. In both groups, after ASA challenge, 12-HETE rose to similar levels while 5-HETE and LTB4 remained unchanged. These data do not support the concept that an abnormality in the regulation of arachidonic acid oxidative pathways in ASA-sensitive asthmatics is a generalized phenomenon which embraces the platelets and leucocytes; rather it is inhibition of cyclo-oxygenase within the tissues of the respiratory tract that triggers asthmatic attacks in the sensitive patients.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Arachidonate 12-Lipoxygenase; Arachidonic Acids; Aspirin; Asthma; Blood Platelets; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukocytes; Leukotriene B4; Male; Middle Aged

In a child with primary thrombocythaemia, observations have been made over a period of five years, during which, transient apparently thrombotic events occurred in the central nervous system on several occasions. Spontaneous platelet aggregation was noted and deaggregation took place even after exposure to ADP in vitro. Associated findings included pronounced elevation in plasma levels of 6-keto-PGF1 alpha and 6-keto-PGE1, the latter described for the first time. Production of 12-HETE by platelets was markedly reduced, probably reflecting lipoxygenase deficiency which has been reported in other myeloproliferative disorders. It has been suggested that 12-HETE is a natural inhibitor of thromboxane synthetase, so the further finding of enormous generation of TxA2, measured as TxB2, by this patient's platelets may be explicable. It is suggested that the increase in TxA2 is responsible for spontaneous platelet aggregation. In response to these massive events, there is a production of 6-keto-PGE1 which in turn, promotes platelet deaggregation. Administration of aspirin resulted in symptomatic relief and complete inhibition of TxB2 production.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 6-Ketoprostaglandin F1 alpha; Alprostadil; Arachidonate 12-Lipoxygenase; Aspirin; Asthma; Blood Platelets; Child; Eosinophilia; Humans; Hydroxyeicosatetraenoic Acids; Male; Platelet Aggregation; Thrombocytosis; Thromboxane A2

Purified serum samples from asthmatic and psoriatic patients and healthy controls were analysed by high-pressure liquid chromatography (HPLC) and the amounts of leukotrienes were measured from the corresponding HPLC fractions by specific radioimmunoassays. In the serum of healthy controls the amounts of leukotrienes B4, C4 and D4 were very small or negligible. Rather great amount of leukotriene B4 was, however, detected in the serum of many asthmatic and psoriatic patients. The amount of leukotriene B4 was in the serum of asthmatic patients 120 +/- 20 pmol/ml (n = 11, mean +/- SEM) and in that of psoriatic patients 100 +/- 10 pmol/ml (n = 10). The amounts of leukotrienes C4 and D4 were rather small in the serum of most patients. The amount of leukotriene C4 was, however, very high (250 pmol/ml) in the serum of a psoriatic patient. Significant amount of leukotriene D4 was also detected in the serum of this patient. The present study indicated that leukotrienes are formed during blood clotting in the leukocytes of asthmatic and psoriatic patients and that the rate of formation is so high that leukotrienes may have a role in these diseases.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adolescent; Adult; Aged; Asthma; Chromatography, High Pressure Liquid; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Male; Middle Aged; Psoriasis; SRS-A

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

The precise mechanisms(s) responsible for airway hyperreactivity to spasmogenic agents (for example, cholinergic stimulants, alpha-adrenergic agonists, histamine, PGF2 alpha and several other nonspecific stimuli) in asthmatics is not known. Substantial evidence exists fo the mediator, as well as modulatory, roles of the products of arachidonic acid metabolism operating via the cyclo-oxygenase pathway in the pathophysiology of lung diseases. Aspirin and other inhibitors of cyclo-oxygenase induce severe bronchospasm and asthmatic attacks in a significant population of asthmatic patients. This adverse effect of aspirin is often attributed to inhibition of the synthesis and release of defensive "modulatory" endogenous prostaglandins (PGD and PGI2?) in the lungs. Thus, removal of their "negative feedback" mechanism on the allergic release of chemical mediators (e.g., histamine and SRS-A: leukotriene C and D) from lung mast cells could lead to an enhancement of the release of mediators and severity of asthmatic attacks. In addition to these mechanisms, recent work suggests the diversion of arachidonic acid (AA) metabolism via the lipoxygenase pathway (especially after cyclo-oxygenase inhibition by aspirin and indomethacin), thereby leading to the formation of a new class of biologically active lipids: hydroperoxy acids (HPETE and HETE), leukotrienes (LTA, B, C, D, E) and SRS or SRS-A (LTC, LTD). The inherent or drug (aspirin)-induced deficiency or blockade of cyclo-oxygenases(s) and/or peroxidases in the lungs (and/or other body tissues, including leukocytes) leading to diversion of AA into the formation and accumulation of SRS (leukotrienes), especially in sensitive individuals, could explain the mechanism of aspirin-induced asthma, and probably the generalized syndrome of aspirin-tolerance. Furthermore, the hydroperoxy acids, leukotrienes, (SRS) may also sensitize receptors for other mediators and common nonspecific irritants, and/or induce airway contractions directly. Collectively, these mechanisms could account for airway hyperreactivity in asthma.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonic Acids; Aspirin; Asthma; Autacoids; Humans; Leukotrienes; Lipid Peroxides; Lipoxygenase; Peroxides; Prostaglandin-Endoperoxide Synthases