ToxSci Advance Access originally published online on February 18, 2003
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Toxicological Sciences 72, 43-56 (2003)
Copyright © 2003 by the Society of Toxicology
CARCINOGENICITY |
Role of Neutrophils in the Synergistic Liver Injury from Monocrotaline and Bacterial Lipopolysaccharide Exposure
,
,1
* Department of Pharmacology and Toxicology;
Department of Veterinary Pathology, National Food Safety and Toxicology Center; and
Institute for Environmental Toxicology, Michigan State University, East Lansing, Michigan 48824
Synergistic liver injury develops in Sprague-Dawley rats from administration of a small, noninjurious dose (7.4 x 106 EU/kg) of bacterial lipopolysaccharide (LPS) given 4 h after a nontoxic dose (100 mg/kg) of the pyrrolizidine alkaloid, monocrotaline (MCT). Previous studies demonstrated that liver injury is mediated through inflammatory factors, such as Kupffer cells and tumor necrosis factor 
(TNF-), rather than through simple interaction between MCT and LPS. In the present study, the hypothesis that neutrophils (polymorphonuclear leukocytes or PMNs) are causally involved in this injury model is tested, and the interdependence between PMNs and other inflammatory components is explored. Hepatic PMN accumulation and the appearance of cytokine-induced neutrophil chemoattractant-1 in plasma preceded the onset of liver injury, suggesting that PMNs contribute to toxicity. Hepatic PMN accumulation was partially dependent on TNF-. Prior depletion of PMNs in MCT/LPS-cotreated animals resulted in attenuation of both hepatic parenchymal cell (HPC) and sinusoidal endothelial cell (SEC) injury at 18 h. PMN depletion did not, however, protect against early SEC injury that occurred before the onset of HPC injury at 6 h. This observation suggests that SEC injury is not entirely dependent on PMNs in this model. In vitro, MCT caused PMNs to degranulate in a concentration-dependent manner. These results provide evidence that PMNs are critical to the HPC injury caused by MCT/LPS cotreatment and contribute to the progression of SEC injury.
Key Words: liver; inflammation; lipopolysaccharide; monocrotaline; neutrophil; sinusoidal endothelial cells; cytokine-induced neutrophil chemoattractant.
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