5-oxo-6-8-11-14-eicosatetraenoic-acid and Inflammation

Protectin D1 (PD1) is an anti-inflammatory and proresolving lipid mediator biosynthesized from the omega-3 fatty acid docosahexaenoic acid (DHA). Exogenous PD1 conferred protection against eosinophilic inflammation in animals with experimental asthma, although its endogenous cellular source and functions in human airways are of interest.. We sought to investigate the synthesizing capacity of PD1 in eosinophils from healthy subjects and patients with severe asthma and its direct effects on eosinophil functions.. Human eosinophil-derived metabolites of arachidonic acid and DHA were analyzed with liquid chromatography-tandem mass spectrometry-based lipidomic analysis. The biological activities of PD1 on the function of human eosinophils, including chemotaxis, adhesion molecule expressions, degranulation, superoxide anion generation, or survival, were examined.. We identified PD1 as one of the main anti-inflammatory and proresolving molecules synthesized in human eosinophils. PD1, in nanomolar concentrations, suppressed the chemotaxis induced by CCL11/eotaxin-1 or 5-oxo-eicosatetraenoic acid and modulated the expression of the adhesion molecules CD11b and L-selectin, although it had no effects on the degranulation, superoxide anion generation, or survival of the eosinophils. Compared with the cells harvested from healthy subjects, we observed a prominent decrease in the biosynthesis of PD1 by eosinophils from patients with severe asthma, even in presence of DHA.. These observations are a first indication that activated human eosinophils represent a major source of PD1, which can act as a self-resolving machinery in eosinophilic inflammation, whereas the production of PD1 is impaired in patients with severe asthma.

Topics: Adult; Aged; Anti-Inflammatory Agents; Arachidonic Acids; Asthma; Case-Control Studies; CD11b Antigen; Cell Adhesion Molecules; Chemokine CCL11; Chemotaxis; Docosahexaenoic Acids; Eosinophils; Female; Humans; Inflammation; L-Selectin; Male; Neutrophils; Superoxides

The eicosanoid 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) has recently been identified as the ligand for the oxoeicosanoid (OXE) receptor. In vitro and in vivo studies have suggested that 5-oxo-ETE has a role in the asthmatic inflammatory response and it has been shown to stimulate eosinophil migration to the airways. New data suggest that eosinophils have an important role in the pathogenesis of asthma, being required for mucus accumulation, airway hyperresponsiveness and remodelling of the airways. However, there are several mediators that can stimulate the recruitment of eosinophils to the airways and the development of antagonists against the OXE receptor is required to evaluate the potential of the OXE receptor as a new therapeutic approach for asthma.

Topics: Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Asthma; Bronchial Hyperreactivity; Chemotactic Factors; Eosinophils; Humans; Inflammation; Models, Biological; Monocytes; Neutrophils

5-Oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid) is a highly potent granulocyte chemoattractant that acts through a selective G-protein coupled receptor. It is formed by oxidation of the 5-lipoxygenase product 5-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid) by 5-hydroxyeicosanoid dehydrogenase (5-HEDH). Although leukocytes and platelets display high microsomal 5-HEDH activity, unstimulated intact cells do not convert 5-HETE to appreciable amounts of 5-oxo-ETE. To attempt to resolve this dilemma we explored the possibility that 5-oxo-ETE synthesis could be enhanced by oxidative stress. We found that hydrogen peroxide and t-butyl hydroperoxide strongly stimulate 5-oxo-ETE formation by U937 monocytic cells. This was dependent on the GSH redox cycle, as it was blocked by depletion of GSH or inhibition of glutathione reductase and mimicked by oxidation of GSH to GSSG by diamide. Glucose inhibited the response to H2O2 through its metabolism by the pentose phosphate pathway, as its effect was reversed by the glucose-6-phosphate dehydrogenase inhibitor dehydroepiandrosterone. 5-Oxo-ETE synthesis was also strongly stimulated by hydroperoxides in blood monocytes, lymphocytes, and platelets, but not neutrophils. Unlike monocytic cells, lymphocytes and platelets were resistant to the inhibitory effects of glucose. 5-Oxo-ETE synthesis following incubation of peripheral blood mononuclear cells with arachidonic acid and calcium ionophore was also strongly enhanced by t-butyl hydroperoxide. Oxidative stress could act by depleting NADPH, resulting in the formation NADP+, the cofactor for 5-HEDH. This is opposed by the pentose phosphate pathway, which converts NADP+ back to NADPH. Oxidative stress could be an important mechanism for stimulating 5-oxo-ETE production in inflammation, promoting further infiltration of granulocytes into inflammatory sites.

Topics: Arachidonate 5-Lipoxygenase; Arachidonic Acids; Blood Platelets; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Eosinophils; Glucose; Glucose-6-Phosphate; Glutathione; Glutathione Reductase; Hexoses; Humans; Hydrogen Peroxide; Inflammation; Leukocytes; Lymphocytes; Models, Biological; Monocytes; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxygen; Pentose Phosphate Pathway; tert-Butylhydroperoxide; Time Factors; U937 Cells