title: Airway epithelial cells synthesize the lipid mediator 5-oxo-ETE in response to oxidative stress.
abstract: 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a potent eosinophil chemoattractant that is synthesized from the 5-lipoxygenase product 5S-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) by the NADP+-dependent enzyme 5-hydroxyeicosanoid dehydrogenase (5-HEDH), previously reported only in inflammatory cells. Because of their critical location at the interface of the lung with the external environment, we sought to determine whether epithelial cells could also synthesize this substance. We found that HEp-2, T84, A549, and BEAS-2B cells all synthesize 5-oxo-ETE from 5-HETE in amounts comparable to leukocytes. The epithelial dehydrogenase is localized in the microsomal fraction, requires NADP+, and is selective for the S-isomer of 5-HETE, suggesting that it is identical to leukocyte 5-HEDH. Normal human bronchial epithelial cells have an even greater capacity to synthesize 5-oxo-ETE. H2O2 dramatically stimulates its synthesis in association with increased levels of intracellular GSSG and NADP+. These responses were all blocked by removal of GSH/GSSG with N-ethylmaleimide, suggesting that H2O2 stimulates 5-oxo-ETE synthesis by raising NADP+ levels through activation of the GSH redox cycle. Airway smooth muscle cells can also synthesize 5-oxo-ETE, but to a lesser extent. These results suggest that epithelial cells may be a major source of 5-oxo-ETE under conditions of oxidative stress, which may contribute to eosinophil infiltration in allergic diseases.
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, 3626 St. Urbain Street, Montreal, Quebec, Canada H2X 2P2.
authors.forename: Karl-Rudolf
authors.initials: KR
authors.lastname: Erlemann
authors.forename: Chantal
authors.initials: C
authors.lastname: Cossette
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gravel
authors.forename: Alain
authors.initials: A
authors.lastname: Lesimple
authors.forename: Gue-Jae
authors.initials: GJ
authors.lastname: Lee
authors.forename: Goutam
authors.initials: G
authors.lastname: Saha
authors.forename: Joshua
authors.initials: J
authors.lastname: Rokach
authors.forename: William S
authors.initials: WS
authors.lastname: Powell
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D001095:Arachidonic Acids / Q000096:biosynthesis*; D001980:Bronchi / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D012132:Respiratory Muscles / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid; D009249:NADP; D006861:Hydrogen Peroxide; D000429:Alcohol Oxidoreductases; C099244:5-hydroxyeicosanoid dehydrogenase; D005978:Glutathione