Neutrophil elastase inhibitor (sivelestat) reduces the levels of inflammatory mediators by inhibiting NF-kB.
OBJECTIVE
Sivelestat sodium hydrate (sivelestat) is a specific synthetic inhibitor of neutrophil elastase (NE). Various studies suggest that sivelestat treatment reduces inflammation. In this study, we tested the hypothesis that sivelestat acts as an inhibitor of inflammatory mediators and prevents nuclear factor-kB (NF-kB) activation.


METHODS
In the presence and absence of sivelestat, the mouse macrophage cell line RAW 264.7 was stimulated with lipopolysaccharide (LPS) and the levels of inflammatory mediators (TNF-alpha, IL-6 and high mobility group box 1 (HMGB1)) and nitrite in the cell supernatant were measured, along with inducible nitric oxide synthase (iNOS) expression.


RESULTS
While LPS administration increased the secretion of inflammatory mediators and nitric oxide (NO), sivelestat decreased the secretion of these mediators. Cell signaling studies demonstrated that sivelestat decreased NF-kB activation by inhibiting IkB phosphorylation.


CONCLUSIONS
Sivelestat may inhibit the various inflammatory mediators through NF-kB inhibition.
Hagiwara
S
S
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi, Yufu City, Oita, 879-5593, Japan. saku@med.oita-u.ac.jp
Iwasaka
H
H
Hidaka
S
S
Hasegawa
A
A
Noguchi
T
T
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D015842:Serine Proteinase Inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides / Q000378:metabolism*
D016207:Cytokines; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009573:Nitrites; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C069195:sivelestat; D052247:Nitric Oxide Synthase Type II; D019272:Leukocyte Elastase; D005998:Glycine