Neutrophil elastase inhibitors, SC-37698 and SC-39026, reduce endotoxin- induced lung dysfunction in awake sheep

James R Gossage, Y. Kuratomi, J. M. Davidson, P. L. Lefferts, J. R. Snapper

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Neutrophils have been implicated as important cellular mediators of the pulmonary dysfunction observed following endotoxemia in chronically instrumented awake sheep. Several areas of research suggest that neutrophil- derived proteases may be mediators of this dysfunction. We hypothesized that neutrophil elastase inhibitors would attenuate the effects of endotoxemia in sheep. To test this hypothesis, we studied the effects of two putative neutrophil elastase inhibitors, SC-37698 and SC-39026 (Searle, Skokie, IL), on endotoxin-induced lung dysfunction in awake sheep. Sheep were given intravenous neutrophil elastase inhibitor alone (20 mg/kg/h for 6 h), intravenous endotoxin (E. coli endotoxin, 0.5 μg/kg over 20 min) 1 h after beginning the 6-h infusion of elastase inhibitor, or endotoxin 1 h after beginning a 6-h infusion of elastase inhibitor vehicle. SC-37698 attenuated the increase in lung lymph flow and lung lymph protein clearance, the alterations in lung mechanics, and the fall in white blood count. Qualitatively similar effects were seen with SC-39026. These data suggest the need for further research examining the role of protease-antiprotease interactions and the potential utility of neutrophil elastase inhibitors in acute lung injury like that observed in the adult respiratory distress syndrome (ARDS) in the human.

Original languageEnglish (US)
Pages (from-to)1371-1379
Number of pages9
JournalAmerican Review of Respiratory Disease
Volume147
Issue number6 I
StatePublished - Jan 1 1993
Externally publishedYes

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Secretory Proteinase Inhibitory Proteins
Endotoxins
Sheep
Lung
Endotoxemia
Pancreatic Elastase
Lymph
Neutrophils
Peptide Hydrolases
Acute Lung Injury
Adult Respiratory Distress Syndrome
Protease Inhibitors
Mechanics
Research
lodelaben
SC 37698
Escherichia coli
Proteins

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Neutrophil elastase inhibitors, SC-37698 and SC-39026, reduce endotoxin- induced lung dysfunction in awake sheep. / Gossage, James R; Kuratomi, Y.; Davidson, J. M.; Lefferts, P. L.; Snapper, J. R.

In: American Review of Respiratory Disease, Vol. 147, No. 6 I, 01.01.1993, p. 1371-1379.

Research output: Contribution to journalArticle

Gossage, James R ; Kuratomi, Y. ; Davidson, J. M. ; Lefferts, P. L. ; Snapper, J. R. / Neutrophil elastase inhibitors, SC-37698 and SC-39026, reduce endotoxin- induced lung dysfunction in awake sheep. In: American Review of Respiratory Disease. 1993 ; Vol. 147, No. 6 I. pp. 1371-1379.
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