Inhibition of inducible nitric oxide synthase worsens liver damage regardless of lipopolysaccharide treatment in small-for-size liver transplantation.
OBJECTIVE
In small-for-size liver transplantation, portal hypertension aggravates endotoxin from the gut which accelerates the activation of inducible nitric oxide synthase (iNOS). However, there is little knowledge as to the effects of iNOS inhibitors on small-for-size graft damage. Our study was designed to investigate the role of an iNOS inhibitor both with and without lipopolysaccharide (LPS) treatment in ischemia-reperfusion injury of small-for-size liver transplantation.


METHODS
Subjecting Sprague-Dawley rats to small-for-size grafts liver transplantation, we investigated the time course of changes in hepatic expression of iNOS and endothelial nitric oxide synthase (eNOS). Meantime, we also investigated the effects of iNOS inhibitor, both with and without LPS treatment, at 6h after reperfusion.


RESULTS
While iNOS mRNA expression reached a peak at 3h, the highest protein level occurred at 6h after reperfusion. Aminoguanidine (AG) significantly inhibited mRNA and protein expressions of iNOS, but not that of eNOS. However, LPS accelerated activation of iNOS, but suppressed the expression of eNOS. Meanwhile, compared with the untreated group, those treated with AG or LPS experienced worsened liver function and tissue damage, promoting neutrophil infiltration in the liver tissue. The difference between the LPS group and the LPS+AG group was found to be significant. In addition, AG and LPS treatments up-regulated the protein expression of ICAM-1 and NF-kappaB p65.


CONCLUSIONS
In a small-for-size model of rat liver transplantation, regardless of LPS treatment, the inhibitor of iNOS, AG, attenuated iNOS expression, but worsened liver function and tissue damage. The subsequent increased neutrophil infiltration in liver tissue may be associated with up-regulation of ICAM-1 and NF-kappaB expressions.
Hu
MingZheng
M
Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China.
Wang
ZhilLiang
Z
Rao
JianHua
J
Cao
Yang
Y
Jiang
WeiWei
W
Zhang
Feng
F
Li
XiangCheng
X
Wang
XueHao
X
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D008070:Lipopolysaccharides / Q000627:therapeutic use*; D008099:Liver / Q000473:pathology*; D008107:Liver Diseases / Q000188:drug therapy* / Q000201:enzymology*; D016031:Liver Transplantation; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D015996:Survival Rate
D000276:Adjuvants, Immunologic; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II