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

Abstract

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. © 2007 Nature Publishing Group All rights reserved.