Transcriptional activation of heme oxygenase-1 and its functional significance in acetaminophen-induced hepatitis and hepatocellular injury in the rat

Background/Aim: Glutathione depletion contributes to acetaminophen hepatoto xicity and is known to induce the oxidative stress reactant heme oxygenase- 1, The metabolites of the heme oxygenase pathway, biliverdin, carbon monoxi de, and iron may modulate acetaminophen toxicity, The aim of this study was to assess cell-type specific expression of heme oxygenase-l and its impact on liver injury and microcirculatory disturbances in a model of acetaminop hen-induced hepatitis. Methods: Gene expression of heme oxygenase-l was studied by Northern- and W estern analysis as well as immunohistochemistry. The time course of heme ox ygenase-l and -2, cytokine-induced neutrophil chemoattractant-l, and interc ellular adhesion molecule-1 was studied by Northern analysis, DNA-binding a ctivity of nuclear factor-kappa B was determined by electrophoretic mobilit y shift assay. Sinusoidal perfusion and leukocyte-endothelia; interactions were assessed by intravital microscopy, Results: Acetaminophen caused a moderate sinusoidal perfusion failure (-15% ) and infiltration of neutrophils along with activation of nuclear factor-k appa B and intercellular adhesion molecule-1 and cytokine-induced neutrophi l chemoattractant-1 mRNAs, Induction of heme oxygenase-1 mRNA and protein ( similar to 30fold) in hepatocytes and non-parenchymal cells paralleled the inflammatory response. Blockade of heme oxygenase activity with tin-proeopo rphyrin-IX abrogated acetaminophen-induced hepatic neutrophil accumulation and nuclear factor-kappa B activation, but failed to affect sinusoidal perf usion and liver injury, Conclusions: The inflammatory response associated with acetaminophen hepato toxicity is modulated by the parallel induction of the heme oxygenase-l gen e. However, heme oxygenase-l has no permissive effect on sinusoidal perfusi on and does not affect liver injury in this model. These data argue against a central role of nuclear factor-kappa B activation and neutrophil infiltr ation as perpetuating factors of liver injury in acetaminophen toxicity.