Neutrophil Elastase Inhibitors, SC-37698 and SC-39026, Reduce Endotoxin-induced Lung Dysfunction in Awake Sheep

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 microgram/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.

A critical role for neutrophil elastase in experimental bullous pemphigoid

“…NE has been implicated in numerous inflammatory diseases (22,(43)(44)(45)(46)(47). Using NE-null mutant mice, we now provide evidence that NE plays a destructive role in experimental BP, an inflammatory skin blistering disease.…”

Intermittent High-Permeability Hemofiltration Modulates Inflammatory Response in Septic Patients with Multiorgan Failure

“…However, an overabundant activation of PML may have devastating effects. Activated PMLs bind to endothelial cells and migrate toward tissues, where they initiate inflammation and favor vascular endothelium damage and organ dysfunction [13, 14, 15]. …”

Transepithelial Migration of Neutrophils

“…The BAL fluid (132)(133)(134)(135) and plasma (136) of patients with ALI/ARDS are characterized by high levels of elastase, and these levels correlate with the severity of lung injury (134,136). In animal models, elastase administration causes lung injury (137)(138)(139) and elastase inhibition has a protective effect on lung injury (140)(141)(142)(143)(144), as measured by several variables including permeability of the alveolocapillary membrane. There is also strong evidence to support the pathogenic role of elastase in the pathogenesis of inflammatory bowel disease (145)(146)(147)(148) as well as cystic fibrosis (138,149,150) and chronic obstructive pulmonary disease (151,152).…”