This article is part of the supplement: 11th International Symposium on the Cells of the Hepatic Sinusoid and their Relation to Other Cells

Proceedings

Peroxynitrite formation and sinusoidal endothelial cell injury during acetaminophen-induced hepatotoxicity in mice

Tamara R Knight^1,2 and Hartmut Jaeschke^1,2

¹Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA

²Liver Research Institute, University of Arizona College of Medicine, Room 6309, 1501 N. Campbell Avenue, Arizona 85724, USA

author email corresponding author email

Comparative Hepatology 2004, 3(Suppl 1):S46doi:10.1186/1476-5926-2-S1-S46

Published:	14 January 2004

Abstract

Introduction

Vascular injury and accumulation of red blood cells in the space of Disse (hemorrhage) is a characteristic feature of acetaminophen hepatotoxicity. However, the mechanism of nonparenchymal cell injury is unclear. Therefore, the objective was to investigate if either Kupffer cells or intracellular events in endothelial cells are responsible for the cell damage.

Results

Acetaminophen treatment (300 mg/kg) caused vascular nitrotyrosine staining within 1 h. Vascular injury (hemorrhage) occurred between 2 and 4 h. This paralleled the time course of parenchymal cell injury as shown by the increase in plasma alanine aminotransferase activities. Inactivation of Kupffer cells by gadolinium chloride (10 mg/kg) had no significant effect on vascular nitrotyrosine staining, hemorrhage or parenchymal cell injury. In contrast, treatment with allopurinol (100 mg/kg), which prevented mitochondrial injury in hepatocytes, strongly attenuated vascular nitrotyrosine staining and injury.

Conclusions

Our data do not support the hypothesis that acetaminophen-induced superoxide release leading to vascular peroxynitrite formation and endothelial cell injury is caused by activated Kupffer cells. In contrast, the protective effect of allopurinol treatment suggests that, similar to the mechanism in parenchymal cells, mitochondrial oxidant stress and peroxynitrite formation in sinusoidal endothelial cells may be critical for vascular injury after acetaminophen overdose.