Jr. Gossage et al., NEUTROPHIL ELASTASE INHIBITORS, SC-37698 AND SC-39026, REDUCE ENDOTOXIN-INDUCED LUNG DYSFUNCTION IN AWAKE SHEEP, The American review of respiratory disease, 147(6), 1993, pp. 1371-1379
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.