Attenuation of small-for-size liver graft injury by FTY720: significance of cell-survival Akt signaling pathway.
To investigate the protective mechanism of FTY720 in small-for-size liver grafts, we applied a rat orthotopic liver transplantation model using 40% of liver grafts. FTY720 was administered (1 mg/kg, i.v.) at 20 min before graft harvesting in the donor, immediately before total hepatectomy and immediately after graft reperfusion in the recipient. The 7-day graft survival rates in the FTY720 group were significantly improved compared with the control group [100% (6/6) vs. 40% (4/10), p = 0.034]. FTY720 significantly reduced serum ALT and AST levels at 24 h after liver transplantation. The cell-survival Akt signaling pathway was activated in FTY720 groups by phosphorylation of Glycogen Synthase Kinase-3beta, Bad and Forkhead Transcription Factor at 6 and 24 h after liver transplantation. The cleaved-caspases 3, 7 and 9 were down-regulated, accompanied with less apoptotic nuclei after FTY720 treatment. Acute-phase inflammatory MAPK pathway was down-regulated by dephosphorylation of c-Raf, Mek and Erk in the treatment groups. A20 and endothelial nitric oxide synthase were up-regulated together with down-regulation of iNOS. Hepatic sinusoids were well preserved in the FTY720 group but disrupted in the control group. In conclusion, FTY720 attenuates small-for-size liver graft injury by activation of cell-survival Akt signaling and down-regulation of the MAPK pathway.
Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China.
Yi
Y
Zhao
Kwan
K
Man
Chung Mau
CM
Lo
Kevin T
KT
Ng
Xian Liang
XL
Li
Chris K
CK
Sun
Terence K
TK
Lee
Xian Wei
XW
Dai
Sheung Tat
ST
Fan
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D000068876:Fingolimod Hydrochloride; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008099:Liver / Q000033:anatomy & histology*; D016031:Liver Transplantation / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D011409:Propylene Glycols / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives; D014157:Transcription Factors / Q000378:metabolism; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D011505:Protein-Tyrosine Kinases; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine