title: Augmenter of liver regeneration attenuates inflammatory response in the postischemic mouse liver in vivo.
abstract: BACKGROUND
  Augmenter of Liver Regeneration (ALR), a protein synthesized in the liver is suggested to be protective against oxidative stress-induced cell death. Hepatic ischemia-reperfusion (I/R) injury is triggered by reactive oxygen species. Here, we tested the hypothesis that ALR attenuates hepatic I/R injury in vivo.
  
  
  METHODS
  C57BL6 mice were subjected to warm hepatic ischemia for 90 min. Either recombinant ALR (100 μg/kg) or vehicle were administered to mice prior ischemia. During reperfusion, neutrophil and CD4+ T cell migration and sinusoidal perfusion were analyzed using intravital microscopy. Alanine aminotransferase-aspartate aminotransferase (plasma) and caspase-3 (tissue) activities were determined as markers of hepatocellular necrotic and apoptotic injury.
  
  
  RESULTS
  Hepatic I/R led to dramatic enhancement of neutrophil and CD4+ T cell recruitment in hepatic microvessels, sinusoidal perfusion failure, and strong elevation of aspartate aminotransferase-alanine aminotransferase and caspase-3 activities. During early reperfusion (60 min), the pretreatment with ALR improved postischemic perfusion failure (P < 0.05) and attenuated liver enzyme activities. Recruitment of CD4+ T cells, but not of neutrophils was attenuated. After 240 min of reperfusion, the protective effect of ALR was stronger, since the liver enzyme activity, perfusion failure, and leukocyte influx were significantly attenuated. As shown by the measurement of caspase-3 activity, postischemic apoptosis was reduced in the ALR-treated group.
  
  
  CONCLUSIONS
  Our in vivo data show that ALR has a therapeutic potential against postischemic liver injury. As a mechanism, we suggest a direct protective effect of ALR on apoptotic and necrotic death of hepatocytes and an attenuation of inflammatory cell influx into the postischemic tissue.
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany. Electronic address: Andrej.Khandoga@med.uni-muenchen.de.
authors.forename: Andrej
authors.initials: A
authors.lastname: Khandoga
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany; Walter-Brendel Centre for Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mende
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Emil
authors.initials: E
authors.lastname: Iskandarov
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Rosentreter
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Celine
authors.initials: C
authors.lastname: Schelcher
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany; Walter-Brendel Centre for Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Jöerg
authors.initials: J
authors.lastname: Reifart
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Jauch
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D005260:Female; D008102:Liver Circulation / Q000276:immunology; D008115:Liver Regeneration / Q000187:drug effects / Q000276:immunology*; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000276:immunology; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D018384:Oxidative Stress / Q000276:immunology*; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000276:immunology* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D015427:Reperfusion Injury / Q000188:drug therapy / Q000276:immunology*
chemical_list: D011994:Recombinant Proteins; D050862:Oxidoreductases Acting on Sulfur Group Donors; C551231:GFER protein, mouse
keywords: Inflammation; Ischemia–reperfusion; Liver microcirculation; Neutrophils; Perfusion failure; T cells