title: 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.
authors.affiliation: Department of Immunology, Women's and Children's Hospital, North Adelaide, South Australia.
authors.forename: E J
authors.initials: EJ
authors.lastname: Bates
authors.forename: A
authors.initials: A
authors.lastname: Ferrante
authors.forename: D P
authors.initials: DP
authors.lastname: Harvey
authors.forename: M
authors.initials: M
authors.lastname: Nandoskar
authors.forename: A
authors.initials: A
authors.lastname: Poulos
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003571:Cytochalasin B / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis; D005227:Fatty Acids / Q000494:pharmacology; D006801:Humans; D007958:Leukocyte Count / Q000187:drug effects; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology* / Q000502:physiology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000502:physiology*; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D016861:Cyclooxygenase Inhibitors; D005227:Fatty Acids; D016859:Lipoxygenase Inhibitors; D004281:Docosahexaenoic Acids; C059579:methyl docosahexaenoate; D003571:Cytochalasin B; C026704:methoxysuccinyl-alanyl-alanyl-prolyl-valine chloromethyl ketone; D015118:Eicosapentaenoic Acid; D011464:Epoprostenol; D002374:Catalase; D010196:Pancreatic Elastase