EFFECTS OF ONO-5046, A SPECIFIC NEUTROPHIL ELASTASE INHIBITOR, ON ENDOTOXIN-INDUCED LUNG INJURY IN SHEEP

The purpose of the present study was to assess the role of polymorphonuclear leukocyte (neutrophil) elastase in endotoxin-induced acute lung injury in sheep with lung lymph fistula. We studied the effects of ONO-5046, a specific inhibitor of neutrophil elastase, on the lung dysfunction induced by the intravenous infusion of 1 mu g/kg of Escherichia coli endotoxin. Endotoxin alone produced a biphasic response as previously reported. Early (0.5-1 h) after endotoxin, pulmonary arterial pressure increased from 19.5 +/- 0.9 cmH(2)O at baseline to a peak of 46.8 +/- 2.4 cmH(2)O (P < 0.05). Pulmonary vascular resistance increased from 3.03 +/- 0.17 cmH(2)O.l(-1).min at baseline to a peak of 9.77 +/- 0.70 cmH(2)O.l(-1).min (P < 0.05). Circulating neutrophils decreased from 7,355 +/- 434/mm(3) at baseline to a nadir of 1,762 +/- 32/mm(3) (P < 0.05). Thromboxane B-2 and 6-ketoprostaglandin F-1 alpha concentrations in plasma and lung lymph were significantly increased. Late (3-5 h) after endotoxin, pulmonary arterial pressure and pulmonary vascular resistance returned to baseline levels, but lung lymph flow remained increased from 4.2 +/- 0.3 ml/0.5 h at baseline to 7.3 +/- 0.7 ml/0.5 h (P < 0.05), with a slight increase in lung lymph-to-plasma protein concentration ratio, suggesting increased pulmonary vascular permeability. The histopathological features of the lungs during the early period in sheep treated with endotoxin alone revealed a large increase in neutrophils per 100 alveoli and changes of pulmonary edema such as thickening of the interstitium of the lung and alveolar flooding. The continuous intravenous infusion of ONO-5046 at 10 mg.kg(-1).h(-1) blocked most of the lung dysfunction and histopathological changes of the lungs induced by endotoxin. We conclude that neutrophil elastase might have a crucial role in the pathogenesis of endotoxin-induced acute lung injury in sheep.