Neutrophil elastase inhibitor reduces neutrophil chemoattractant production after ischemia-reperfusion in rat liver.
OBJECTIVE
Neutrophils are important in the development of tissue injury induced by ischemia-reperfusion. The ability of an inhibitor of neutrophil elastase (ONO-5046) to protect against ischemia-reperfusion injury in rat liver was investigated by measuring serum concentrations of cytokine-induced neutrophil chemoattractant.


METHODS
Liver ischemia was induced in rats by occluding the portal vein for 30 minutes, and ONO-5046 or anticoagulants were injected intravenously 5 minutes before vascular clamping.


RESULTS
Serum concentration of cytokine-induced neutrophil chemoattractant increased after reperfusion, reached a maximum at 6 hours, and then gradually decreased. However, pretreatment of animals with heparin (50 U/kg), antithrombin III (250 U/kg), or ONO-5046 (10 mg/kg) resulted in significantly smaller increases in the serum concentration of cytokine-induced neutrophil chemoattractant after reperfusion. Pretreatment with both ONO-5046 and heparin, or both ONO-5046 and antithrombin III, produced additive effects. Pretreatment of rats with both ONO-5046 and heparin or both ONO-5046 and antithrombin III also inhibited the increase in cytokine-induced neutrophil chemoattractant mRNA in liver. These combined treatments significantly reduced the increases in both the number of neutrophils accumulated in the liver and the hepatic activity of myeloperoxidase.


CONCLUSIONS
Cytokine-induced neutrophil chemoattractant production after ischemia-reperfusion in the liver is mediated by neutrophil elastase and activation of coagulation within the hepatic microcirculation.
Yamaguchi
Y
Y
Department of Surgery II, Kumamoto University Medical School, Japan.
Akizuki
E
E
Ichiguchi
O
O
Matsumura
F
F
Goto
M
M
Miyanari
N
N
Mori
K
K
Yamada
S
S
Ogawa
M
M
D000818:Animals; D000990:Antithrombin III / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000378:metabolism; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis* / Q000235:genetics; D004357:Drug Synergism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006133:Growth Substances / Q000096:biosynthesis* / Q000235:genetics; D006493:Heparin / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D007511:Ischemia / Q000378:metabolism*; D007958:Leukocyte Count; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008102:Liver Circulation; D008297:Male; D009504:Neutrophils / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D000990:Antithrombin III; D006493:Heparin; C069195:sivelestat; D009195:Peroxidase; D001219:Aspartate Aminotransferases; D019272:Leukocyte Elastase; D005998:Glycine