title: Antileukoproteinase protects against hepatic inflammation, but not apoptosis in the response of D-galactosamine-sensitized mice to lipopolysaccharide.
abstract: OBJECTIVE
  There is major evidence for the strong bi-directional interrelation of parenchymal cell apoptosis and leukocyte accumulation and inflammation in acute liver injury. Therefore, the aim of this in vivo study was to investigate the anti-apoptotic and anti-inflammatory potential of antileukoproteinase (ALP) in a murine model of acute liver failure.
  
  
  METHODS
  C57BL/6J mice were given galactosamine (D-GalN) and E. coli lipopolysaccharide (LPS) followed by administration of saline or ALP. Besides survival rate, hepatic tissue damage and inflammatory response were analyzed by intravital fluorescence microscopy 6 hours after treatment. In addition, immunohistochemical analysis of NFkappaB-p65 and hepatocellular apoptosis, plasma levels of AST/ALT, TNF-alpha and IL-10 were determined.
  
  
  RESULTS
  Administration of D-GalN/LPS provoked hepatic damage, including marked leukocyte recruitment and microvascular perfusion failure, as well as hepatocellular apoptosis and enzyme release. NFkappaB-p65 became increasingly detectable in hepatocellular nuclei, accompanied by a rise of TNF-alpha and IL-10 plasma levels. ALP markedly reduced intrahepatic leukocyte accumulation, nuclear translocation of NFkappaB and plasma levels of TNF-alpha and IL-10. Moreover, liver enzyme levels indicated the absence of necrotic parenchymal cell death. In contrast, ALP failed to block both apoptosis and caspase-3 levels and the mortality rate of ALP-treated animals was comparable to that of saline-treated mice.
  
  
  CONCLUSIONS
  ALP could effectively prevent D-GalN/LPS-associated intrahepatic inflammatory responses by inhibition of NFkappaB activity, but not apoptosis-driven mortality. Thus, a protease-inactivating approach such as application of ALP seems to be inadequate in damaged liver where apoptosis represents the predominant mode of cell death.
authors.affiliation: Institute for Experimental Surgery, University of Rostock, Rostock, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Eipel
authors.forename: E
authors.initials: E
authors.lastname: Kidess
authors.forename: K
authors.initials: K
authors.lastname: Abshagen
authors.forename: K
authors.initials: K
authors.lastname: Leminh
authors.forename: M D
authors.initials: MD
authors.lastname: Menger
authors.forename: H
authors.initials: H
authors.lastname: Burkhardt
authors.forename: B
authors.initials: B
authors.lastname: Vollmar
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D005260:Female; D005688:Galactosamine / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000097:blood / Q000401:mortality / Q000517:prevention & control*; D016753:Interleukin-10 / Q000097:blood; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence / Q000379:methods; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000008:administration & dosage / Q000494:pharmacology*; D016019:Survival Analysis; D015996:Survival Rate; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D008070:Lipopolysaccharides; D053481:Secretory Leukocyte Peptidase Inhibitor; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D005688:Galactosamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase