8-11-14-eicosatrienoic-acid and Cystic-Fibrosis

Eicosanoids are a group of bioactive lipids that are shown to be important mediators of neutrophilic inflammation; selective targeting of their function confers therapeutic benefit in a number of diseases. Neutrophilic airway diseases, including cystic fibrosis, are characterized by excessive neutrophil infiltration into the airspace. Understanding the role of eicosanoids in this process may reveal novel therapeutic targets. The eicosanoid hepoxilin A3 is a pathogen-elicited epithelial-produced neutrophil chemoattractant that directs transepithelial migration in response to infection. Following hepoxilin A3-driven transepithelial migration, neutrophil chemotaxis is amplified through neutrophil production of a second eicosanoid, leukotriene B4 (LTB4). The rate-limiting step of eicosanoid generation is the liberation of arachidonic acid by phospholipase A2, and the cytosolic phospholipase A2 (cPLA2)α isoform has been specifically shown to direct LTB4 synthesis in certain contexts. Whether cPLA2α is directly responsible for neutrophil synthesis of LTB4 in the context of

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Antigens, Human Platelet; Cell Communication; Cell Line; Chemotaxis; Coculture Techniques; Cystic Fibrosis; Cytosol; Humans; Leukotriene B4; Mice; Neutrophils; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Mucosa; Tomography, Optical Coherence; Transendothelial and Transepithelial Migration

Recurrent Pseudomonas aeruginosa infections coupled with robust, damaging neutrophilic inflammation characterize the chronic lung disease cystic fibrosis (CF). The proresolving lipid mediator, 15-epi lipoxin A

Topics: 8,11,14-Eicosatrienoic Acid; Bacterial Proteins; Bronchoalveolar Lavage Fluid; Cell Line; Crystallography, X-Ray; Cystic Fibrosis; Humans; Inflammation; Lipoxins; Lung Diseases; Neutrophil Activation; Neutrophils; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Virulence Factors

Pulmonary exacerbations in cystic fibrosis airways are accompanied by inflammation, neutrophilia, and mucous thickening. Cystic fibrosis sputum contains a large amount of uncleared DNA contributed by neutrophil extracellular trap (NET) formation from neutrophils. The exact mechanisms of the induction of NETosis in cystic fibrosis airways remain unclear, especially in uninfected lungs of patients with early cystic fibrosis lung disease. Here we show that Hepoxilin A3, a proinflammatory eicosanoid, and the synthetic analog of Hepoxilin B3, PBT-3, directly induce NETosis in human neutrophils. Furthermore, we show that Hepoxilin A3-mediated NETosis is NADPH-oxidase-dependent at lower doses of Hepoxilin A3, while it is NADPH-oxidase-independent at higher doses. Together, these results demonstrate that Hepoxilin A3 is a previously unrecognized inducer of NETosis in cystic fibrosis lungs and may represent a new therapeutic target for treating cystic fibrosis and other inflammatory lung diseases.

Topics: 8,11,14-Eicosatrienoic Acid; Cells, Cultured; Cystic Fibrosis; Extracellular Traps; Humans; Neutrophils

Some but not all studies have reported abnormal polyunsaturated fatty acid composition in cystic fibrosis (CF) patients. We investigated the influence of pancreatic status and sex on the fatty acid profile in plasma and erythrocyte membranes in patients with CF.. After a 1-step transesterification with acetyl chloride on plasma and washed erythrocyte membranes, we quantified fatty acid methyl esters by use of GC-MS in 124 CF patients and 80 age-matched healthy controls. In the CF group, mean (SD) age was 17.5 (11.3) years, and 51.6% were male. Pancreatic insufficiency was diagnosed in 78% of the CF population.. A decrease in docosahexaenoic acid concentrations was observed in CF patients independently of pancreatic status. Pancreatic insufficient CF patients displayed lower concentrations of linoleic acid and arachidonic acid and higher concentrations of dihomo-gamma-linolenic acid and eicosatrienoic acid (mead acid) in plasma and erythrocyte membranes compared with healthy controls and pancreatic sufficient CF patients. Male CF patients had significantly lower docosahexaenoic acid and higher eicosatrienoic acid in plasma and erythrocyte membranes compared with female CF patients.. These results support the concept that multiple abnormalities of polyunsaturated fatty acid composition participate in the CF disease phenotype and that pancreatic status plays a major role in such abnormalities. Moreover, patient sex influences the polyunsaturated fatty acid spectrum in CF, with more marked abnormalities in males.

Topics: 8,11,14-Eicosatrienoic Acid; Adolescent; Arachidonic Acid; Cystic Fibrosis; Docosahexaenoic Acids; Erythrocyte Membrane; Exocrine Pancreatic Insufficiency; Fatty Acids, Unsaturated; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Plasma; Sex Factors

A study of plasmatic fatty acids was carried out on a group of paediatric patients suffering from cystic fibrosis. These data have been compared with those obtained by others authors. High levels of saturated fatty acids and a reduction of polyunsaturates have been found. The ratio of eicosatrienoic acid to arachidonic acid is high in this group of patients, which indicates a certain lack of essential fatty acids.

Topics: 8,11,14-Eicosatrienoic Acid; Adolescent; Arachidonic Acid; Arachidonic Acids; Child; Child, Preschool; Cystic Fibrosis; Dietary Fats; Fatty Acids; Female; Humans; Infant; Linoleic Acid; Linoleic Acids; Male; Nutrition Disorders