title: Benefit of Kupffer cell modulation with glycine versus Kupffer cell depletion after liver transplantation in the rat: effects on postischemic reperfusion injury, apoptotic cell death graft regeneration and survival.
abstract: Inhibition or destruction of Kupffer cells (KC) may protect against ischemia-reperfusion (IR) induced primary graft nonfunction (PNF) in liver transplantation. Besides KC activation, PNF is characterized by microvascular perfusion failure, intrahepatic leukocyte accumulation, cell death and hepatocellular dysfunction. KCs can be inactivated by different agents including gadolinium chloride (GdCl3), methyl palmitate (MP) and glycine. The effects of three KC inactivators on IR-injury after rat liver transplantation were compared in the present study. Lewis liver donors were treated with GdCl3, MP, glycine or saline (control). Liver grafts were transplanted following 24 h storage (UW solution). KC populations and IR damage were assessed by histologic analysis, quantitative real-time polymerase chain reaction (RT-PCR) and intravital microscopy. The number of hepatic ED-1 positive macrophages was diminished after GdCl3 (114.8+/-4.4/mm2 liver tissue) and MP treatment (176.0+/-5.0), versus the glycine (263.9+/-5.5) and control (272.1+/-5.6) groups. All three treatment modalities downregulated phagocytic activity for latex particles, paralleled by reduced microvascular injury (acinar perfusion index, GdCl3: 0.75+/-0.03; MP: 0.83+/-.03; glycine: 0.84+/-0.03; 0.63+/-0.03). Quantitative RT-PCR revealed elevated myeloperoxidase mRNA after glycine versus GdCl3 and MP pretreatment (3.2- and 3.4-fold, P=0.011, respectively), without difference to controls (2.9-fold of glycine). TNFalpha-mRNA was reduced after glycine- (5.2-fold), GdCl3- (19.7-fold), MP-treatment (39.5-fold) compared with controls. However, profound prevention of intrahepatic cell death and liver graft failure was solely achieved with glycine preconditioning. Different than GdCl3 and MP, glycine modulates rather than destroys KCs. Glycine appears to preserve cell viability and to TNFalpha/leukocyte dependent organ regeneration capacity, which is related to increase graft survival following liver transplantation.
authors.affiliation: Department of Surgery, Ludwig-Maximilians University of Munich, Klinikum Grosshadern, Munich, Germany. markus.rentsch@med.uni-muenchen.de
authors.forename: Markus
authors.initials: M
authors.lastname: Rentsch
authors.forename: Kerstin
authors.initials: K
authors.lastname: Puellmann
authors.forename: Slawo
authors.initials: S
authors.lastname: Sirek
authors.forename: Igors
authors.initials: I
authors.lastname: Iesalnieks
authors.forename: Klaus
authors.initials: K
authors.lastname: Kienle
authors.forename: Thomas
authors.initials: T
authors.lastname: Mueller
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bolder
authors.forename: Edward
authors.initials: E
authors.lastname: Geissler
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Jauch
authors.forename: Alexander
authors.initials: A
authors.lastname: Beham
mesh_terms: D000818:Animals; D017209:Apoptosis; D001646:Bile / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D005682:Gadolinium / Q000627:therapeutic use; D005998:Glycine / Q000627:therapeutic use*; D006085:Graft Survival; D007728:Kupffer Cells / Q000187:drug effects / Q000502:physiology*; D007962:Leukocytes / Q000502:physiology; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D016031:Liver Transplantation; D008297:Male; D010168:Palmitates / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D012038:Regeneration; D015427:Reperfusion Injury / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D010168:Palmitates; D014409:Tumor Necrosis Factor-alpha; D005682:Gadolinium; C019012:methyl palmitate; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C038958:gadolinium chloride; D005998:Glycine