Effects of ONO-1078, a peptide leukotriene antagonist, on endotoxin-induced acute lung injury.
The role of lipoxygenase metabolites in the pathogenesis of endotoxin (LPS)-induced lung injury remains to be clarified. We investigated the contribution of peptide leukotrienes to LPS-induced acute lung injury using a potent antagonist, ONO-1078 (ONO). Experimental groups consisted of a saline group (n = 10), an LPS group (n = 9) injected intravenously with 2 mg E. coli LPS, an ONO group (n = 8) receiving 30 mg/kg of intraperitoneal ONO, and an LPS+ONO group (n = 6) receiving 30 mg/kg of ONO intraperitoneally 10 min before the LPS injection. The [125I]albumin lung plasma ratio, which is a parameter of acute lung injury, was significantly increased (p < 0.01) in the LPS group compared with the saline, ONO, and LPS+ONO groups. The [125I]albumin BAL fluid plasma ratio was also increased (p < 0.01) in the LPS group compared with the other groups. ONO pretreatment attenuated the LPS-induced increases in neutrophil counts in the BAL fluid. In vitro studies showed that ONO suppresses the neutrophil chemotaxis induced by LTB4, zymosan-activated serum, and FMLP. We conclude that (1) ONO-1078 attenuates LPS-induced acute lung injury; and (2) this effect appears mainly a result of its potent antagonistic actions against peptide leukotrienes and also, in part, the suppression of neutrophil chemotaxis.
Ishizaka
A
A
Department of Medicine, School of Medicine, Keio University, Japan.
Hasegawa
N
N
Sakamaki
F
F
Tasaka
S
S
Nakamura
H
H
Kishikawa
K
K
Yamada
A
A
Obata
T
T
Sayama
K
K
Urano
T
T
D000418:Albumins / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002634:Chemotaxis, Leukocyte; D002867:Chromones / Q000494:pharmacology*; D004731:Endotoxins; D004926:Escherichia coli; D005260:Female; D006168:Guinea Pigs; D007958:Leukocyte Count; D008070:Lipopolysaccharides; D008168:Lung / Q000473:pathology; D009113:Muramidase / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D009929:Organ Size; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013481:Superoxides / Q000378:metabolism
D000418:Albumins; D002867:Chromones; D004731:Endotoxins; D008070:Lipopolysaccharides; D013189:SRS-A; D013481:Superoxides; D009113:Muramidase; C047681:pranlukast