Impaired hepatic regeneration by ischemic preconditioning in a rat model of small-for-size liver transplantation.
OBJECTIVE
Graft size is one of the major risk factors in adult-to-adult living donor liver transplantation and rapid regeneration is an essential post-operative requirement. Ischemic preconditioning (IPC) has been shown to be an effective strategy in the reduction of hepatic ischemia-reperfusion injury and stimulation of liver regeneration. This study was designed to evaluate the effects of IPC on liver regeneration in small-for-size liver grafts.


METHODS
We employed a rat orthotopic liver transplantation model using small-for-size (30%) grafts, in the presence or absence (control) of IPC (10 min of ischemia followed by 15 min of reperfusion). Survival rate, graft injury, hepatocellular proliferation, cell cycle progression, Stat3 activation, as well as TNF-alpha and IL-6 expression were assessed.


RESULTS
IPC significantly enhanced the extent of graft injury and hindered hepatic regeneration in small-for-size liver grafts. The 7-day survival rate was also reduced by IPC, but failed to reach statistical significance. IPC did not affect TNF-alpha levels, but significantly decreased the elevation of IL-6 after reperfusion. These findings were correlated with down-regulation of cyclin E and cyclin D1, and decreased numbers of PCNA-positive nuclei in IPC grafts. These results were inconsistent with Stat3 activation, as P-Stat3 exhibited a stronger and prolonged pattern of expression in the IPC group, compared to controls.


CONCLUSIONS
Ischemic preconditioning may impair liver regeneration in small-for-size liver grafts by decreasing IL-6 and blunting cell cycle progression, through a mechanism at least partially independent of Stat3.
Yao
AiHua
A
Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 GuangZhou Road, Nanjing, 210029, China.
Li
XiangCheng
X
Pu
LiYong
L
Zhong
JiWei
J
Liu
XianZhong
X
Yu
Yue
Y
Zhang
Feng
F
Kong
LianBao
L
Sun
BeiCheng
B
Wang
XueHao
X
D000818:Animals; D002453:Cell Cycle; D015850:Interleukin-6 / Q000502:physiology; D019194:Ischemic Preconditioning; D008099:Liver / Q000473:pathology; D008115:Liver Regeneration; D016031:Liver Transplantation; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D023421:Models, Animal; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D015850:Interleukin-6; D018809:Proliferating Cell Nuclear Antigen; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D014409:Tumor Necrosis Factor-alpha