Glutathione peroxidase-deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: Importance of an intracellular oxidant stress

Neutrophils contribute to hepatocellular injury in a number of acute inflam matory reactions. However, the molecular mechanism of parenchymal cell inju ry remains controversial. To address the issue of whether or not reactive o xygen species (ROS) are important in the injury process, we used the galact osamine/endotoxin (Gal/ET) model of acute liver failure, which involves a n eutrophil-mediated parenchymal cell injury. In C3Heb/FeJ mice, Gal/ET induc ed a significant increase of hepatic and plasma levels of glutathione disul fide (GSSG), an indicator of oxidant stress, selectively during the neutrop hil-mediated injury phase, In glutathione peroxidase-deficient mice (Gpx1(- /-)), Gal/ET or Gal/tumor necrosis factor alpha (TNF-alpha) caused more sev ere neutrophil-mediated liver injury compared with wild-type animals. Howev er, there was no significant difference in other critical parameters, e.g., activation Of the transcription factor, nuclear factor-kappa B (NF-kappa B ), and soluble intercellular adhesion molecule-1 (sICAM-1), parenchymal cel l apoptosis, and neutrophil sequestration in the liver, Our results suggest that neutrophil-derived ROS are responsible for an intracellular oxidant s tress in hepatocytes after Gal/ET treatment. Because of the higher suscepti bility of Gpx1-/- mice to a neutrophil-mediated injury, we conclude that pe roxides generated by neutrophils diffused into hepatocytes and contributed to parenchymal cell death in vivo. Thus, strengthening defense mechanisms a gainst ROS in target cells can attenuate excessive inflammatory injury with out affecting host defense reactions.