Adenoviral cardiotrophin-1 transfer improves survival and early graft function after ischemia and reperfusion in rat small-for-size liver transplantation model.
This study was to investigate the effect of donor liver adenoviral cardiotrophin-1 (CT-1) gene transfer on early graft survival and function in rat small-for-size liver transplantation. We constructed a recombinant murine CT-1 adenoviral vector. Donor rats were transduced in vivo with adenoviruses expressing CT-1 (AdCT-1) or control vector (AdEGFP). Livers were harvested 4 days later, reduced to 40% of weight, and transplanted. A syngeneic rat orthotopic liver transplantation model was performed using 40% small-for-size grafts. Graft survival, liver function, hepatic architecture change, the degree of necrosis and apoptosis, and cell survival signaling pathways were assessed. AdCT-1 pretreatment markedly improved liver function and the survival of small-for-size grafts. In the CT-1 treatment group, hepatic architecture was well protected, apoptotic and necrotic cells were reduced; anti-apoptotic protein bcl-2 was up-regulated and pro-apoptotic cleaved caspase-3 was down-regulated, cell survival signaling pathways were activated by phosphorylation of protein kinase B (Akt), extracellular-regulated kinase (ERK) and Signal transducer and activator of transcription-3 (Stat-3) after transplantation. In conclusion, donor liver adenoviral CT-1 transfer ameliorated ischemia/reperfusion injury by decreasing hepatic necrosis and apoptosis in small-for-size liver transplantation, mediated in part by activation of the Akt, ERK, and Stat-3 survival signaling pathways. These results may provide a potential clinical strategy to improve the outcome of small-for-size liver grafts.
Song
Jun
J
The Liver Transplantation Center of the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China. songjunwk@yahoo.com.cn
Zhang
Ye-Wei
YW
Yao
Ai-Hua
AH
Yu
Yue
Y
Hua
Zhi-Yuan
ZY
Pu
Li-Yong
LY
Li
Guo-Qiang
GQ
Li
Xiang-Cheng
XC
Zhang
Feng
F
Sheng
Guo-Qing
GQ
Wang
Xue-Hao
XH
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D016207:Cytokines / Q000235:genetics*; D015870:Gene Expression; D006085:Graft Survival / Q000502:physiology*; D016031:Liver Transplantation / Q000502:physiology*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury; D015398:Signal Transduction; D014161:Transduction, Genetic
D016207:Cytokines; C092073:cardiotrophin 1