Antileukoproteinase protects against hepatic inflammation, but not apoptosis in the response of D‐galactosamine‐sensitized mice to lipopolysaccharide

• Published in: British journal of pharmacology Vol. 151; no. 3; pp. 406 - 413
• Main Authors: Eipel, C, Kidess, E, Abshagen, K, LeMinh, K, Menger, M D, Burkhardt, H, Vollmar, B
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2007; Nature Publishing; Nature Publishing Group
• Subjects: Alanine Transaminase - blood; Animals; apoptosis; Apoptosis - drug effects; Apoptosis - immunology; Aspartate Aminotransferases - blood; Biological and medical sciences; Blotting, Western; Cell Adhesion - drug effects; Female; Galactosamine - administration & dosage; Galactosamine - immunology; Galactosamine - pharmacology; Humans; Immunohistochemistry; inflammation; Inflammation - blood; Inflammation - mortality; Inflammation - prevention & control; Interleukin-10 - blood; Leukocytes - cytology; Leukocytes - drug effects; Lipopolysaccharides - administration & dosage; Lipopolysaccharides - pharmacology; liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Medical sciences; Mice; Mice, Inbred C57BL; microcirculation; Microscopy, Fluorescence - methods; neutrophils; Pharmacology. Drug treatments; Research Papers; rodent; Secretory Leukocyte Peptidase Inhibitor - administration & dosage; Secretory Leukocyte Peptidase Inhibitor - pharmacology; Survival Analysis; Survival Rate; Transcription Factor RelA - metabolism; Tumor Necrosis Factor-alpha - blood; Galactosamine; Digestive system; Liver; Rodentia; Inflammation; Prevention; Microcirculation; Vertebrata; Mammalia; Mouse; Cell death; Animal; rodent; Lipopolysaccharide; Neutrophil; neutrophils; Apoptosis
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0707230

Background and purpose: 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. Experimental approach: 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 NFκB‐p65 and hepatocellular apoptosis, plasma levels of AST/ALT, TNF‐α and IL‐10 were determined. Key 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. NFκB‐p65 became increasingly detectable in hepatocellular nuclei, accompanied by a rise of TNF‐α and IL‐10 plasma levels. ALP markedly reduced intrahepatic leukocyte accumulation, nuclear translocation of NFκB and plasma levels of TNF‐α 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 and implications: ALP could effectively prevent D‐GalN/LPS‐associated intrahepatic inflammatory responses by inhibition of NFκB 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. British Journal of Pharmacology (2007) 151, 406–413; doi:10.1038/sj.bjp.0707230