Abstract
IntroductionVascular 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.ResultsAcetaminophen 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.ConclusionsOur 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.
Highlights
Vascular injury and accumulation of red blood cells in the space of Disse is a characteristic feature of acetaminophen hepatotoxicity
A dose of 300 mg/kg AAP had no effect on liver tissue at 1 h but caused severe centrilobular necrosis with hemorrhage at 6 h (Figure 1)
Immunohistochemical staining for nitrotyrosine, an indicator for peroxynitrite formation, demonstrated selective staining of vascular lining cells at 1 h after AAP (Figure 1)
Summary
Vascular injury and accumulation of red blood cells in the space of Disse (hemorrhage) is a characteristic feature of acetaminophen hepatotoxicity. The mechanism of nonparenchymal cell injury is unclear. An overdose of AAP causes centrilobular necrosis, which in severe cases can lead to liver failure, in both experimental animals and humans [1,2]. Excessive NAPQI formation results in covalent binding to sulfhydryl groups of proteins [2,4]. Protein binding is a critical early event in AAP hepatotoxicity, this mechanism alone cannot explain the severe cell injury. AAP treatment leads to Kupffer cell activation [5] and recruitment of neutrophils into the liver [6]. AAP metabolism causes mitochondrial dysfunction [7,8,9], which results in mitochondrial oxidant stress [10] and peroxynitrite formation (page number not for citation purposes)
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