title: A potent inhibitor of cytosolic phospholipase A2, arachidonyl trifluoromethyl ketone, attenuates LPS-induced lung injury in mice.
abstract: Acute respiratory distress syndrome (ARDS) is an acute lung injury of high mortality rate, and sepsis syndrome is one of the most frequent causes of ARDS. Metabolites of arachidonic acid, including thromboxanes and leukotrienes, are proinflammatory mediators and potentially involved in the development of ARDS. A key enzyme for the production of these inflammatory mediators is cytosolic phospholipase A(2) (cPLA(2)). Recently, it has been reported that arachidonyl trifluoromethyl ketone (ATK) is a potent inhibitor of cPLA(2). In the present study, we hypothesized that pharmacological intervention of cPLA(2) could affect acute lung injury. To test this hypothesis, we examined the effects of ATK in a murine model of acute lung injury induced by septic syndrome. The treatment with ATK significantly attenuated lung injury, polymorphonuclear neutrophil sequestration, and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration. The current observations suggest that pharmacological intervention of cPLA(2) could be a novel therapeutic approach to acute lung injury caused by sepsis syndrome.
authors.affiliation: Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Japan. takahide-tky@umin.ac.jp
authors.forename: Takahide
authors.initials: T
authors.lastname: Nagase
authors.forename: Naonori
authors.initials: N
authors.lastname: Uozumi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Aoki-Nagase
authors.forename: Kan
authors.initials: K
authors.lastname: Terawaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishii
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Tomita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Kohei
authors.initials: K
authors.lastname: Hashizume
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ouchi
authors.forename: Takao
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017997:Leukotriene C4 / Q000032:analysis; D017998:Leukotriene D4 / Q000032:analysis; D017999:Leukotriene E4 / Q000032:analysis; D008070:Lipopolysaccharides; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D012965:Sodium Chloride; D013929:Thromboxane B2 / Q000032:analysis; D015054:Zymosan
chemical_list: D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C081565:arachidonyltrifluoromethane; D017997:Leukotriene C4; D012965:Sodium Chloride; D013929:Thromboxane B2; D017998:Leukotriene D4; D017999:Leukotriene E4; D015054:Zymosan; D009195:Peroxidase; D010741:Phospholipases A; D054467:Phospholipases A2