FTY720 pretreatment reduces warm hepatic ischemia reperfusion injury through inhibition of T-lymphocyte infiltration.
Ischemia and reperfusion (IR) injury remains a significant problem in clinical liver transplantation. We investigated the effects of lymphocyte depletion with FTY720 in models of warm hepatic IR. Using 60-min partial warm hepatic IR, three groups of rats were studied: Sham--laparotomy alone; Control--water p.o. x 3 d before ischemia; Treatment--FTY720 p.o. x 3 d before ischemia. Animals were sacrificed for analysis at 6 h and 24 h post reperfusion. The effect of FTY720 pretreatment on survival was also studied using 150 min total hepatic IR with portojugular shunt. FTY720 treatment significantly reduced serum glutamic pyruvic transaminase and peripheral blood lymphocytes compared to controls at 6h and 24h (p < 0.0005). Histological grade was significantly improved in treated livers vs. controls (p < 0.05). CD3 immunocytochemical analysis revealed a significant reduction in T-cell infiltration in FTY720-treated livers (p < 0.0002). No difference in tissue myeloperoxidase levels was observed. Seven-day survival was significantly improved in treated rats vs. controls following total hepatic ischemia (p < 0.05). In conclusion, FTY720 ameliorates the biochemical and histological manifestations of hepatic IR by preventing T-lymphocyte infiltration and prolongs survival following a more severe ischemic insult. Myeloperoxidase data suggest this mechanism is independent of neutrophil activation. These results indicate that T lymphocytes are pivotal mediators in hepatic IR and may have important implications in liver transplantation.
Anselmo
Dean M
DM
Dumont-UCLA Transplant Center, UCLA School of Medicine, Los Angeles, CA 90095-7054, USA.
Amersi
Farin F
FF
Shen
Xiu-Da
XD
Gao
Feng
F
Katori
Masamichi
M
Lassman
Charles
C
Ke
Bibo
B
Coito
Ana J
AJ
Ma
Jeffrey
J
Brinkmann
Volker
V
Busuttil
Ronald W
RW
Kupiec-Weglinski
Jerzy W
JW
Farmer
Douglas G
DG
D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D000068876:Fingolimod Hydrochloride; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000276:immunology; D008297:Male; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000276:immunology / Q000517:prevention & control*; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine