Endothelin-1 aggravates hepatic ischemia/reperfusion injury during obstructive cholestasis in bile duct ligated mice.
BACKGROUND
Cholestasis of the liver is known to be an important risk factor for surgical morbidity and mortality after major hepatectomy. However, the mechanism of liver injury in cholestatic liver is not fully understood. The goal of this study was to investigate the process of liver injury due to hepatic ischemia/reperfusion in obstructive cholestasis.


METHODS
Male C57BL/6 mice underwent common bile duct ligation and subsequently developed obstructive cholestasis. The mice were subjected to 90 min of partial hepatic ischemia followed by reperfusion.


RESULTS
The survival rate of the mice with cholestatic livers after hepatic ischemia/reperfusion was lower than that of the mice with normal livers. Biochemical and histological analyses showed that the cholestatic mice had a much higher degree of hepatocellular injury after reperfusion than the normal mice. Neutrophil accumulation after reperfusion was significantly decreased in the cholestatic livers; however, considerable microcirculatory disturbances were observed in cholestatic livers after reperfusion. Hepatic stellate cell activation and hepatic expression of endothelin-1 were evaluated by immunohistochemical staining in cholestatic livers after reperfusion. These observations were also associated with increased serum levels of endothelin-1.


CONCLUSIONS
Hepatic stellate cell activation and increased endothelin-1 production play a crucial role in hepatic ischemia/reperfusion injury in cholestatic liver.
Nagai
Hiroyuki
H
Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
Kato
Atsushi
A
Kimura
Fumio
F
Shimizu
Hiroaki
H
Yoshidome
Hiroyuki
H
Ohtsuka
Masayuki
M
Furukawa
Katsunori
K
Nozawa
Satoshi
S
Yoshitomi
Hideyuki
H
Mitsuhashi
Noboru
N
Takeuchi
Dan
D
Suda
Kosuke
K
Yoshioka
Isaku
I
Miyazaki
Masaru
M
D000818:Animals; D019743:Chemokines, CXC / Q000378:metabolism; D002779:Cholestasis / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D003135:Common Bile Duct / Q000601:surgery; D019332:Endothelin-1 / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D008026:Ligation; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism
D019743:Chemokines, CXC; D019332:Endothelin-1