NEUTROPHIL ELASTASE INHIBITORS, SC-37698 AND SC-39026, REDUCE ENDOTOXIN-INDUCED LUNG DYSFUNCTION IN AWAKE SHEEP

Neutrophils have been implicated as important cellular mediators of th e pulmonary dysfunction observed following endotoxemia in chronically instrumented awake sheep. Several areas of research suggest that neutr ophil-derived proteases may be mediators of this dysfunction. We hypot hesized that neutrophil elastase inhibitors would attenuate the effect s of endotoxemia in sheep. To test this hypothesis, we studied the eff ects of two putative neutrophil elastase inhibitors, SC-37698 and SC-3 9026 (Searle, Skokie, IL), on endotoxin-induced lung dysfunction in aw ake sheep. Sheep were given intravenous neutrophil elastase inhibitor alone (20 mg/kg/h for 6 h), intravenous endotoxin (E. coli endotoxin, 0.5 mug/kg over 20 min) 1 h after beginning the 6-h infusion of elasta se inhibitor, or endotoxin 1 h after beginning a 6-h infusion of elast ase inhibitor vehicle. SC-37698 attenuated the increase in lung lymph flow and lung lymph protein clearance, the alterations in lung mechani cs, and the fall in white blood count. Qualitatively similar effects w ere seen with SC-39026. These data suggest the need for further resear ch examining the role of protease-antiprotease interactions and the po tential utility of neutrophil elastase inhibitors in acute lung injury like that observed in the adult respiratory distress syndrome (ARDS) in the human.