title: Selective eicosanoid-generating capacity of cytoplasmic phospholipase A2 in Pseudomonas aeruginosa-infected epithelial cells.
abstract: Airway neutrophil infiltration is a pathological hallmark observed in multiple lung diseases including pneumonia and cystic fibrosis. Bacterial pathogens such as Pseudomonas aeruginosa instigate neutrophil recruitment to the air space. Excessive accumulation of neutrophils in the lung often contributes to tissue destruction. Previous studies have unveiled hepoxilin A(3) as the key molecular signal driving neutrophils across epithelial barriers. The eicosanoid hepoxilin A(3) is a potent neutrophil chemoattractant produced by epithelial cells in response to infection with P. aeruginosa. The enzyme phospholipase A(2) liberates arachidonic acid from membrane phospholipids, the rate-limiting step in the synthesis of all eicosanoids, including hepoxilin A(3). Once generated, aracidonic acid is acted upon by multiple cyclooxygenases and lipoxygenases producing an array of functionally diverse eicosanoids. Although there are numerous phospholipase A(2) isoforms capable of generating arachidonic acid, the isoform most often associated with eicosanoid generation is cytoplasmic phospholipase A(2)α. In the current study, we observed that the cytoplasmic phospholipase A(2)α isoform is required for mediating P. aeruginosa-induced production of certain eicosanoids such as prostaglandin E(2). However, we found that neutrophil transepithelial migration induced by P. aeruginosa does not require cytoplasmic phospholipase A(2)α. Furthermore, P. aeruginosa-induced hepoxilin A(3) production persists despite cytoplasmic phospholipase A(2)α suppression and generation of the 12-lipoxygenase metabolite 12-HETE is actually enhanced in this context. These results suggest that alterative phospholipase A(2) isoforms are utilized to synthesize 12-lipoxygenase metabolites. The therapeutic implications of these findings are significant when considering anti-inflammatory therapies based on targeting eicosanoid synthesis pathways.
authors.affiliation: Mucosal Immunology, Massachusetts General Hospital, Charlestown, 02129, USA. bphurley@partners.org
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Hurley
authors.forename: Waheed
authors.initials: W
authors.lastname: Pirzai
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mumy
authors.forename: Karsten
authors.initials: K
authors.lastname: Gronert
authors.forename: Beth A
authors.initials: BA
authors.lastname: McCormick
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000096:biosynthesis; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D016718:Arachidonic Acid / Q000096:biosynthesis; D001483:Base Sequence; D002460:Cell Line; D003593:Cytoplasm / Q000201:enzymology; D015232:Dinoprostone / Q000096:biosynthesis; D015777:Eicosanoids / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology*; D020556:Neutrophil Infiltration; D054467:Phospholipases A2 / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011550:Pseudomonas aeruginosa; D034741:RNA, Small Interfering / Q000235:genetics; D057705:Transendothelial and Transepithelial Migration
chemical_list: D015777:Eicosanoids; D034741:RNA, Small Interfering; D016718:Arachidonic Acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C038243:8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2; D015126:8,11,14-Eicosatrienoic Acid; D015232:Dinoprostone