Role of inducible nitric oxide synthase in pig liver transplantation.
BACKGROUND
Previously, we clarified the role of inducible nitric oxide synthase (iNOS) and the protective effect of an iNOS inhibitor in warm ischemia and reperfusion model. In this study, we investigated whether the same effects would be obtained by iNOS inhibitor in liver transplantation model.


METHODS
Orthotopic liver transplantation was performed in pigs in the usual manner after about 6 h of cold preservation in University of Wisconsin solution. Aminoguanidine hemisulfate (AG) was used as the iNOS inhibitor and AG was administered intraportally at the dose of 10 mg/kg just after reperfusion. Two experimental groups were subjected, control group (n = 10), and AG group (n = 10). We investigated changes of serum nitrite/nitrate (NOx) and aspartate aminotransferase (AST). Expression of iNOS was examined by immunohistochemistry, including a double immunofluorescnce technique in combination with cofocal laser scanning microscopy.


RESULTS
Serum NOx and AST were significantly lower in the AG group. Histological hepatic damage and thrombocyte thrombi were attenuated in the AG group. Expression of iNOS was recognized strongly at Kupffer cells and neutrophils in the centrilobular region of liver after reperfusion by cofocal laser scanning microscopy. Moreover, iNOS staining was attenuated in AG group compared with control group.


CONCLUSIONS
These results indicate that hepatic ischemia and reperfusion injury in liver transplantation might be triggered by iNOS expression of Kupffer cells and neutrophils, and attenuated by administration of an iNOS inhibitor. Moreover, AG showed down regulation of iNOS expression after reperfusion.
Kimura
Hitoshi
H
First Department of Surgery, Sapporo Medical University, School of Medicine, Sapporo, Japan. kimujin@md.neweb.ne.jp
Katsuramaki
Tadashi
T
Isobe
Masato
M
Nagayama
Minoru
M
Meguro
Makoto
M
Kukita
Kazuma
K
Nui
Akihiro
A
Hirata
Koichi
K
D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D003080:Cold Temperature; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006146:Guanidines / Q000494:pharmacology; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000201:enzymology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D016031:Liver Transplantation; D018613:Microscopy, Confocal; D009336:Necrosis; D009504:Neutrophils / Q000201:enzymology; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D015424:Reperfusion; D013552:Swine; D014021:Tissue Preservation
D004791:Enzyme Inhibitors; D006146:Guanidines; D009566:Nitrates; D009573:Nitrites; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D001219:Aspartate Aminotransferases; C004479:pimagedine