Neutrophil elastase inhibitor (ONO-5046) decreases cytokine-induced neutrophil chemoattractant after reperfusion of pancreaticoduodenal transplantation in rats.
The protective effects of a neutrophil elastase inhibitor (ONO-5046) on reperfusion injury following pancreaticoduodenal transplantation in rats were studied by measuring serum concentrations of cytokine-induced neutrophil chemoattractant (CINC). Male Wistar rats were transplanted with syngeneic pancreaticoduodenal grafts. ONO-5046 was injected intravenously 5 min before vascular clamping and immediately after reperfusion at a dose of 10 mg/kg. No significant differences were observed in the peak serum concentrations of amylase between the groups treated with and treated without ONO-5046. The serum lipase concentrations in the untreated animals increased and peaked 3 hr after reperfusion. ONO-5046 significantly decreased the peak serum lipase concentration. The serum CINC concentrations, which were determined by enzyme-linked immunosorbent assay, increased and peaked 3 hr after reperfusion, decreasing gradually thereafter. However, pretreatment with ONO-5046 significantly inhibited the rise in serum CINC concentrations after reperfusion. Expression of CICN transcripts in the pancrease grafts was evaluated by Northern blot analysis and peaked 3 hr after reperfusion in untreated animals. Pretreatment with ONO-5046 also significantly inhibited the expression of CINC mRNA transcripts in the graft. ONO-5046 significantly decreased the number of neutrophils accumulated in the pancreas graft 24 hr after transplantation. In vitro CINC production by peritoneal macrophages was increased by neutrophil elastase in dose-dependent fashion. However, ONO-5046 decreased CINC production by peritoneal macrophages in response to neutrophil elastase. These results suggest that ONO-5046 prevents early neutrophil accumulation in the pancreas following ischemia/reperfusion of pancreaticoduodenal transplantation.
Wang
F S
FS
Department of Surgery II, Kumamoto University Medical School, Japan.
Yamaguchi
Y
Y
Akizuki
E
E
Miyanari
N
N
Ichiguchi
O
O
Goto
M
M
Mori
K
K
Yamada
S
S
Ogawa
M
M
D000818:Animals; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis* / Q000097:blood; D004386:Duodenum / Q000637:transplantation*; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006133:Growth Substances / Q000096:biosynthesis* / Q000097:blood; D036341:Intercellular Signaling Peptides and Proteins; D019272:Leukocyte Elastase; D008297:Male; D016035:Pancreas Transplantation; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*
D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C069195:sivelestat; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D005998:Glycine