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 consis ted of a saline group (n = 10), an LPS group (n = 9) injected intraven ously with 2 mg E. coil LPS, an ONO group (n = 8) receiving 30 mg/kg o f intraperitoneal ONO, and an LPS + ONO group (n = 6) receiving 30 mg/ kg of ONO intraperitoneally 10 min before the LPS injection. The [I-12 5]albumin lung plasma ratio, which is a parameter of acute rung injury , was significantly increased (p < 0.01) in the LPS group compared wit h the saline, ONO, and LPS + ONO groups. The [I-125]albumin BAL fluid plasma ratio was also increased (p < 0.01) in the LPS group compared w ith the other groups. ONO pretreatment attenuated the LPS-induced incr eases in neutrophil counts in the BAL fluid. in vitro studies showed t hat ONO suppresses the neutrophil chemotaxis induced by LTB(4), zymosa n-activated serum, and FMLP. We conclude that (I) ONO-1078 attenuates LPS-induced acute lung injury; and (2) this effect appears mainly a re sult of its potent antagonistic actions against peptide leukotrienes a nd also, in part, the suppression of neutrophil chemotaxis.