A potent inhibitor of cytosolic phospholipase A2, arachidonyl trifluoromethyl ketone, attenuates LPS-induced lung injury in mice.
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.
Nagase
Takahide
T
Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Japan. takahide-tky@umin.ac.jp
Uozumi
Naonori
N
Aoki-Nagase
Tomoko
T
Terawaki
Kan
K
Ishii
Satoshi
S
Tomita
Tetsuji
T
Yamamoto
Hiroshi
H
Hashizume
Kohei
K
Ouchi
Yasuyoshi
Y
Shimizu
Takao
T
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
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