FTY720 attenuates hepatic ischemia-reperfusion injury in normal and cirrhotic livers.
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.
Man
Kwan
K
Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China. kwanman@hkucc.hku.hk
Ng
Kevin T
KT
Lee
Terence K
TK
Lo
Chung Mau
CM
Sun
Chris K
CK
Li
Xian Liang
XL
Zhao
Yi
Y
Ho
Joanna W
JW
Fan
Sheung Tat
ST
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D015536:Down-Regulation; D019332:Endothelin-1 / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology*; D000068876:Fingolimod Hydrochloride; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D051547:Heme Oxygenase-1; D022781:Hepatocytes / Q000166:cytology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008854:Microscopy, Electron; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011409:Propylene Glycols / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives; D013997:Time Factors; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D048490:raf Kinases / Q000378:metabolism
D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C513296:Cxcl2 protein, rat; D017931:DNA Primers; D019332:Endothelin-1; D018840:HSP70 Heat-Shock Proteins; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D011409:Propylene Glycols; D011506:Proteins; D016753:Interleukin-10; D004815:Epidermal Growth Factor; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine