title: FTY720 pretreatment reduces warm hepatic ischemia reperfusion injury through inhibition of T-lymphocyte infiltration.
abstract: 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.
authors.affiliation: Dumont-UCLA Transplant Center, UCLA School of Medicine, Los Angeles, CA 90095-7054, USA.
authors.forename: Dean M
authors.initials: DM
authors.lastname: Anselmo
authors.forename: Farin F
authors.initials: FF
authors.lastname: Amersi
authors.forename: Xiu-Da
authors.initials: XD
authors.lastname: Shen
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Masamichi
authors.initials: M
authors.lastname: Katori
authors.forename: Charles
authors.initials: C
authors.lastname: Lassman
authors.forename: Bibo
authors.initials: B
authors.lastname: Ke
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Coito
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ma
authors.forename: Volker
authors.initials: V
authors.lastname: Brinkmann
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Farmer
mesh_terms: 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
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine