Am. J. Respir. Crit. Care Med., Vol 150, No. 5, Nov 1994, 1325-1331.
Effects of ONO-1078, a peptide leukotriene antagonist, on endotoxin- induced acute lung injury
A Ishizaka, N Hasegawa, F Sakamaki, S Tasaka, H Nakamura, K Kishikawa, A Yamada, T Obata, K Sayama and T Urano
Department of Medicine, School of Medicine, Keio University, Japan.
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.
