title: In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats.
abstract: OBJECTIVE
  Orthotopic liver transplantation is currently the only curative therapy for chronic end-stage liver disease and acute liver failure. However, a scarcity of cadaveric donors has led to a critical shortage of organs available for transplant. This is further complicated by the prevalence of steatosis in about 13%-50% of donor livers, which is associated with a high risk of dysfunction and primary nonfunction.
  
  
  METHODS
  Steatotic Zucker rat livers and livers from alcohol-fed rats were transplanted into lean control rats. Liver injury, activation of survival signals, and hepatic microcirculation were compared in nontreated and interleukin-6 (IL-6)-treated steatotic isografts.
  
  
  RESULTS
  IL-6 pretreatment of steatotic Zucker rat liver isografts dramatically reduces mortality and liver injury following transplantation. Reperfusion after transplantation induces significant sinusoidal endothelial cell necrapoptosis in steatotic Zucker rat liver isografts, which is prevented by in vitro IL-6 pretreatment. IL-6 treatment activates cell survival signal transducer and activator of transcription factor 3 (STAT3) in hepatocytes and sinusoidal endothelial cells. Laser Doppler imaging and microsphere analyses demonstrate that IL-6 treatment markedly improves hepatic microcirculation, which is impaired in steatotic Zucker rat liver transplants. Finally, in vitro IL-6 treatment of donor livers also markedly reduces mortality associated with fatty liver transplants from alcohol-fed rats.
  
  
  CONCLUSIONS
  IL-6 induces hepatoprotection of steatotic liver isografts via preventing sinusoidal endothelial cell necrapoptosis and consequent amelioration of hepatic microcirculation, and protecting against hepatocyte death. IL-6 pretreatment of steatotic livers may render such allografts useable for clinical transplantation.
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Zlsun@jhmi.edu
authors.forename: Zhaoli
authors.initials: Z
authors.lastname: Sun
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Klein
authors.forename: Svetlana
authors.initials: S
authors.lastname: Radaeva
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.forename: Osama
authors.initials: O
authors.lastname: El-Assal
authors.forename: Hong-Na
authors.initials: HN
authors.lastname: Pan
authors.forename: Barbara
authors.initials: B
authors.lastname: Jaruga
authors.forename: Sandor
authors.initials: S
authors.lastname: Batkai
authors.forename: Sumito
authors.initials: S
authors.lastname: Hoshino
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
authors.forename: George
authors.initials: G
authors.lastname: Kunos
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
mesh_terms: D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004727:Endothelium / Q000166:cytology; D000431:Ethanol / Q000494:pharmacology; D005235:Fatty Liver, Alcoholic / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery*; D006085:Graft Survival / Q000187:drug effects; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000494:pharmacology*; D008099:Liver / Q000098:blood supply / Q000166:cytology / Q000187:drug effects; D008102:Liver Circulation / Q000187:drug effects; D017093:Liver Failure / Q000188:drug therapy / Q000401:mortality / Q000601:surgery; D016031:Liver Transplantation / Q000401:mortality*; D008833:Microcirculation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D050796:STAT3 Transcription Factor; D015996:Survival Rate; D015534:Trans-Activators / Q000378:metabolism; D051020:bcl-X Protein
chemical_list: C494813:Bcl2l1 protein, rat; D002492:Central Nervous System Depressants; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D051020:bcl-X Protein; D000431:Ethanol