Attenuation of small-for-size liver graft injury by FTY720: significance of cell-survival Akt signaling pathway

Am J Transplant. 2004 Sep;4(9):1399-407. doi: 10.1111/j.1600-6143.2004.00527.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Aspartate Aminotransferases / blood
  • Fingolimod Hydrochloride
  • Graft Survival / drug effects
  • Graft Survival / immunology
  • Graft Survival / physiology*
  • Immunosuppressive Agents / therapeutic use*
  • Liver / anatomy & histology*
  • Liver Transplantation / immunology*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Male
  • Propylene Glycols / therapeutic use*
  • Protein Serine-Threonine Kinases / physiology*
  • Protein-Tyrosine Kinases / physiology
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Inbred Lew
  • Signal Transduction
  • Sphingosine / analogs & derivatives
  • Transcription Factors / metabolism
  • Transplantation, Homologous

Substances

  • Immunosuppressive Agents
  • Propylene Glycols
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Protein-Tyrosine Kinases
  • Akt1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Fingolimod Hydrochloride
  • Sphingosine