FTY720 attenuates hepatic ischemia-reperfusion injury in normal and cirrhotic livers

Am J Transplant. 2005 Jan;5(1):40-9. doi: 10.1111/j.1600-6143.2004.00642.x.

Abstract

Hepatic ischemia-reperfusion injury is an inevitable consequence during liver surgery. The outcome is particularly poor in cirrhotic livers, which are more prone to hepatic ischemia-reperfusion injury. We aim to study whether FTY720 could attenuate hepatic ischemia-reperfusion injury both in normal and in cirrhotic livers. We applied a 70% liver-ischemia (60 min) model in rats with normal or cirrhotic livers. FTY720 was given 20 min before ischemia and 10 min before reperfusion (1 mg/kg, i.v.). Liver tissues and blood were sampled at 20 min, 60 min, 90 min, 6 h and 24 h after reperfusion for detection of MAPK-Egr-1, Akt pathways and caspase cascade. Hepatic ultrastructure and apoptosis were also compared. FTY720 significantly improved liver function in the rats with normal and cirrhotic livers. Akt pathway was activated at 6 and 24 h after reperfusion. FTY720 significantly down-regulated Egr-1, ET-1, iNOS and MIP-2 accompanied with up-regulation of A20, IL-10, HO-1 and Hsp70. MAPK (Raf-MEK-Erk) pathway was down-regulated. Hepatic ultrastructure was well maintained and fewer apoptotic liver cells were found in the FTY720 groups. In conclusion, FTY720 attenuates ischemia-reperfusion injury in both normal and cirrhotic livers by activation of cell survival Akt signaling and down-regulation of Egr-1 via Raf-MEK-Erk pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Chemokine CXCL2
  • Chemokines, CXC / metabolism
  • DNA Primers / chemistry
  • Down-Regulation
  • Endothelin-1 / metabolism
  • Epidermal Growth Factor / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibrosis / drug therapy
  • Fibrosis / pathology*
  • Fingolimod Hydrochloride
  • Gene Expression Regulation
  • HSP70 Heat-Shock Proteins / metabolism
  • Heme Oxygenase (Decyclizing) / biosynthesis
  • Heme Oxygenase-1
  • Hepatocytes / cytology
  • Immunosuppressive Agents / pharmacology*
  • In Situ Nick-End Labeling
  • Inflammation
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Interleukin-10 / biosynthesis
  • Liver / drug effects*
  • Liver / injuries
  • Liver / metabolism
  • MAP Kinase Signaling System
  • Male
  • Microscopy, Electron
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Propylene Glycols / pharmacology*
  • Proteins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / drug therapy*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Sphingosine / analogs & derivatives
  • Time Factors
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • raf Kinases / metabolism

Substances

  • Chemokine CXCL2
  • Chemokines, CXC
  • Cxcl2 protein, rat
  • DNA Primers
  • Endothelin-1
  • HSP70 Heat-Shock Proteins
  • Immunosuppressive Agents
  • Intercellular Signaling Peptides and Proteins
  • Propylene Glycols
  • Proteins
  • Interleukin-10
  • Epidermal Growth Factor
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • raf Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Fingolimod Hydrochloride
  • Sphingosine