Protective effect of Sivelestat in a porcine hepatectomy model prepared using an intermittent Pringle method.
The effect of Sivelestat, a neutrophil elastase inhibitor, on hepatic ischemia-reperfusion injury was examined in a pig hepatectomy model. An internal jugular vein-splenic vein bypass was prepared in male pigs and about 40% hepatic resection (left lobe) was performed under 15-min liver ischemia and 5-min intermittent reperfusion. Six animals received Sivelestat (10 mg/kg/h) intravenously and six control animals received physiological saline (10 mg/kg/h) from commencement of laparotomy. Hemodynamics, blood chemistry, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), lactic acid, hyaluronic acid, nitrite/nitrate (NOS), and tumor necrosis factor-alpha (TNF-alpha) were compared between the groups. The effects of Sivelestat on NOS generation and expression of iNOS mRNA and TNF-alpha mRNA were also assessed in J774 cells. Expression of TNF-alpha mRNA in hepatic tissues was examined using RT-PCR. The blood pressure of control animals was significantly lower immediately and 3 h after ischemia-reperfusion, compared with that at commencement of laparotomy, whereas there was no decrease of blood pressure in animals administered Sivelestat. Serum AST (P=0.0045), NOS (P=0.0098), and TNF-alpha (P=0.041) levels were significantly lower 3 h after hepatectomy in animals receiving Sivelestat. Sivelestat inhibited NOS production in J774 cells, but did not inhibit expression of iNOS mRNA or TNF-alpha mRNA. In hepatic tissues, Sivelestat showed a greater tendency to inhibit expression of TNF-alpha mRNA and fewer TUNEL-positive cells were present in the hepatic sinusoidal endothelium after Sivelestat treatment, although these differences were not statistically significant. We conclude that Sivelestat inhibits production of TNF-alpha and NO by inhibiting neutrophil elastase, and thus reduces hepatic injury and stabilizes hemodynamics after ischemia-reperfusion.
Shimoda
Mitsugi
M
Second Department of Surgery, Dokkyo Medical University School of Medicine, 880 Kita Kobayashi, Mibu, Tochigi 321-0293, Japan. mshimoda@dokkyomed.ac.jp <mshimoda@dokkyomed.ac.jp>
Iwasaki
Yoshimi
Y
Okada
Toshie
T
Sawada
Tokihiko
T
Kubota
Keiichi
K
D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D015427:Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C069195:sivelestat; D052247:Nitric Oxide Synthase Type II; D001219:Aspartate Aminotransferases; D019272:Leukocyte Elastase; D005998:Glycine