ONO-5046, AN ELASTASE INHIBITOR, ATTENUATES ENDOTOXIN-INDUCED ACUTE LUNG INJURY IN RABBITS

Endotoxin causes acute lung injury resembling acute respiratory distre ss syndrome. Elastase, as well as reactive oxygen species released fro m activated neutrophils, are thought to play pivotal roles in the path ogenesis of this lung injury. This study investigated whether ONO-5046 , a specific elastase inhibitor, can attenuate acute lung injury induc ed by endotoxin in rabbits. Thirty-two male anesthetized rabbits were randomly assigned to receive one of four treatments (n = 8 for each gr oup): infusion of saline without ONO-5046 treatment (Group S-S), infus ion of saline with ONO-5046 (Group S-O), infusion of Escherichia coli endotoxin (100 mu g/kg over 60 min) without ONO-5046 (Group E-S), and infusion of endotoxin with ONO-5046 (Group E-O). Fifteen minutes befor e the infusion of endotoxin (Groups E-O and E-S) or saline (Groups S-S and S-O), the animals received a bolus injection of ONO-5046 (10 mg/k g) followed by continuous infusion (10 mg.kg(-1).h(-1) Groups S-O and E-O) or saline (Groups S-S and E-S). The lungs of the rabbits were ven tilated with 40% oxygen. Hemodynamics, peripheral leukocyte and platel et counts, and Pao, were recorded during the ventilation period (6 h). Lung mechanics, cell fraction of the bronchoalveolar lavage fluid (BA LF), activated complement, cytokines, and arachidonic acid metabolite concentrations in the BALF were measured at 6 h. The wet- to dry (W/D) -weight ratio of the lung and albumin concentrations in BALF were anal yzed as indices of pulmonary edema. Endotoxin decreased lung complianc e and PaO2, and increased the W/D weight ratio, neutrophil counts, and albumin concentration in the BALF. Concentrations of activated comple ment C5a, interleukin-6, interleukin-8, and thromboxane B-2 in the BAL F were increased by the infusion of endotoxin. ONO-5046 treatment atte nuated these changes. Endotoxin caused extensive morphologic lung dama ge, which was lessened by ONO-5046. In conclusion, intravenous ONO-504 6 pretreatment attenuated endotoxin-induced lung injury in rabbits. Th is beneficial effect of ONO-5046 may be due, in part, to a reduction i n the levels of mediators that activate neutrophils, in addition to th e direct inhibitory effect on elastase.