Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity
Toxicology and Applied Pharmacology
Cytokines; Hypochlorite; Inflammation; NAPDH oxidase; Neutrophils; Oxidant stress
Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-α, interleukin-1β and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose. © 2006 Elsevier Inc. All rights reserved.
Cover, C., Liu, J., Farhood, A., Malle, E., Waalkes, M., Bajt, M., & Jaeschke, H. (2006). Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. Toxicology and Applied Pharmacology, 216 (1). http://dx.doi.org/10.1016/j.taap.2006.04.010