Glutathione peroxidase-deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: Importance of an intracellular oxidant stress
Document Type
Journal Article
Publication Date
2-28-1999
Journal
Hepatology
Volume
29
Issue
2
DOI
10.1002/hep.510290222
Abstract
Neutrophils contribute to hepatocellular injury in a number of acute inflammatory reactions. However, the molecular mechanism of parenchymal cell injury remains controversial. To address the issue of whether or not reactive oxygen species (ROS) are important in the injury process, we used the galactosamine/endotoxin (Gal/ET) model of acute liver failure, which involves a neutrophil-mediated parenchymal cell injury. In C3Heb/FeJ mice, Gal/ET induced a significant increase of hepatic and plasma levels of glutathione disulfide (GSSG), an indicator of oxidant stress, selectively during the neutrophil-mediated injury phase. In glutathione peroxidase-deficient mice (Gpx1(-/-)), Gal/ET or Gal/tumor necrosis factor α (TNF-α) caused more severe neutrophil-mediated liver injury compared with wild-type animals. However, there was no significant difference in other critical parameters, e.g., activation of the transcription factor, nuclear factor-κB (NF-κB), and soluble intercellular adhesion molecule-1 (sICAM-1), parenchymal cell apoptosis, and neutrophil sequestration in the liver. Our results suggest that neutrophil-derived ROS are responsible for an intracellular oxidant stress in hepatocytes after Gal/ET treatment. Because of the higher susceptibility of Gpx1(-/-) mice to a neutrophil-mediated injury, we conclude that peroxides generated by neutrophils diffused into hepatocytes and contributed to parenchymal cell death in vivo. Thus, strengthening defense mechanisms against ROS in target cells can attenuate excessive inflammatory injury without affecting host defense reactions.
APA Citation
Jaeschke, H., Ho, Y., Fisher, M., Lawson, J., & Farhood, A. (1999). Glutathione peroxidase-deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: Importance of an intracellular oxidant stress. Hepatology, 29 (2). http://dx.doi.org/10.1002/hep.510290222