Docosahexanoic acid (22:6, n-3) but not eicosapentaenoic acid (20:5, n-3) can induce neutrophil-mediated injury of cultured endothelial cells: involvement of neutrophil elastase

Abstract

Previously published work has indicated that polyunsaturated fatty acids (PUFA) may enhance neutrophil-mediated damage to host tissues. We have found that endothelial detachment was significantly increased by neutrophils pretreated with docosahexaenoic (22:6, n-3) and arachidonic (20:4, n-6) acids at 10-40 microM but not by eicosapentaenoic acid (20:5, n-3). Endothelial cell lysis as measured by 51Cr release was unaffected. The extent of detachment was dependent on both fatty acid and neutrophil pretreatment concentrations. A specific leukocyte elastase inhibitor abrogated the increased detachment but catalase had no effect. Measurement of prostaglandin I2 synthesis as an alternative nonlytic assay of endothelial function indicated that 20:4 but not 20:5 was able to stimulate neutrophil-induced endothelial PGI2 synthesis. Although all three PUFA (3-33 microM) were found to stimulate release from neutrophil-specific granules, only 22:6 and 20:4 could stimulate release of the azurophilic granules containing elastase to any significant extent. Saturated fatty acids (20:0 and 22:0) and the methyl ester of 22:6 did not cause either neutrophil-mediated endothelial detachment or degranulation. We conclude that neutrophils pretreated with 22:6 or 20:4 but not 20:5 can decrease endothelial integrity through detachment involving neutrophil elastase. These findings may have important implications for the dietary use of fish oils rich in n-3 fatty acids.

Comparison of the Effects of Dietary Saturated, Mono-, and n–6 Polyunsaturated Fatty Acids on Blood Lipid Profile, Oxidant Stress, Prostanoid Synthesis and Aortic Histology in Rabbits

“…Consistent with this report was the finding that enrichment of corn oil in the diet resulted in a dramatic reduction in blood and liver vitamin E content [7]. Another important observation concerning n-6 PUFA was from Bates et al [12] who showed that AA pretreatment of neutrophils decreased endothelial integrity through detachment involving neutrophil elastase.…”

Neutrophil oxygen radical generation. Synergistic responses to tumor necrosis factor and mono/polyunsaturated fatty acids.

“…A number of studies have demonstrated that AA has a major influence on leukocyte responses. AA stimulates the production of oxygen radicals (12, [22][23][24][25][26], release of granule enzymes, increases adherence and damage to the endothelium (26)(27)(28), and inhibits cell migration (13).…”

Regulation of the NADPH oxidase activity and anti-microbial function of neutrophils by arachidonic acid

“…This is attributed to the ability of the delipidated albumin to "extract" the fatty acids from the plasma membrane and perhaps the cell interior. Such a rapid termination of the effects of AA suggests that the fatty acid may be located in the outer leaflet for biological activity or that there is a very rapid reverse transport/diffusion from the cell interior to the outer leaflet and that the native and NEFA, not a metabolite, is responsible for the biological action [10,12].…”