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

Yi Zhao, Kwan Man, Chung Mau Lo, Kevin T. Ng, Xian Liang Li, Chris K. Sun, Kin Wah Lee, Xian Wei Dai, Sheung Tat Fan

Research output: Journal article publicationJournal articleAcademic researchpeer-review

36 Citations (Scopus)

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-3β, 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.
Original languageEnglish
Pages (from-to)1399-1407
Number of pages9
JournalAmerican Journal of Transplantation
Volume4
Issue number9
DOIs
Publication statusPublished - 1 Sep 2004
Externally publishedYes

Keywords

  • Akt survival pathway
  • FTY720
  • Liver transplantation
  • Small-for-size graft

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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