Bauer I, Vollmar B, Jaeschke H, Rensing H, Kraemer T, Larsen R, Bauer M
Department of Anesthesiology and Critical Care Medicine, University of the Saarland, Homburg, Germany.
J Hepatol. 2000 Sep;33(3):395-406. doi: 10.1016/s0168-8278(00)80275-5.
BACKGROUND/AIM: Glutathione depletion contributes to acetaminophen hepatotoxicity and is known to induce the oxidative stress reactant heme oxygenase-1. The metabolites of the heme oxygenase pathway, biliverdin, carbon monoxide, and iron may modulate acetaminophen toxicity. The aim of this study was to assess cell-type specific expression of heme oxygenase-1 and its impact on liver injury and microcirculatory disturbances in a model of acetaminophen-induced hepatitis.
Gene expression of heme oxygenase-1 was studied by Northern- and Western analysis as well as immunohistochemistry. The time course of heme oxygenase-1 and -2, cytokine-induced neutrophil chemoattractant-1, and intercellular adhesion molecule-1 was studied by Northern analysis. DNA-binding activity of nuclear factor-kappaB was determined by electrophoretic mobility shift assay. Sinusoidal perfusion and leukocyte-endothelial interactions were assessed by intravital microscopy.
Acetaminophen caused a moderate sinusoidal perfusion failure (-15%) and infiltration of neutrophils along with activation of nuclear factor-kappaB and intercellular adhesion molecule-1 and cytokine-induced neutrophil chemoattractant-1 mRNAs. Induction of heme oxygenase-1 mRNA and protein (approximately 30-fold) in hepatocytes and non-parenchymal cells paralleled the inflammatory response. Blockade of heme oxygenase activity with tin-protoporphyrin-IX abrogated acetaminophen-induced hepatic neutrophil accumulation and nuclear factor-kappaB activation, but failed to affect sinusoidal perfusion and liver injury.
The inflammatory response associated with acetaminophen hepatotoxicity is modulated by the parallel induction of the heme oxygenase-1 gene. However, heme oxygenase-1 has no permissive effect on sinusoidal perfusion and does not affect liver injury in this model. These data argue against a central role of nuclear factor-kappaB activation and neutrophil infiltration as perpetuating factors of liver injury in acetaminophen toxicity.
背景/目的：谷胱甘肽耗竭会导致对乙酰氨基酚肝毒性，并且已知会诱导氧化应激反应产物血红素加氧酶-1。血红素加氧酶途径的代谢产物，胆绿素、一氧化碳和铁，可能会调节对乙酰氨基酚的毒性。本研究的目的是评估在对乙酰氨基酚诱导的肝炎模型中血红素加氧酶-1的细胞类型特异性表达及其对肝损伤和微循环障碍的影响。
通过Northern印迹和Western印迹分析以及免疫组织化学研究血红素加氧酶-1的基因表达。通过Northern印迹分析研究血红素加氧酶-1和-2、细胞因子诱导的中性粒细胞趋化因子-1以及细胞间黏附分子-1的时间进程。通过电泳迁移率变动分析确定核因子-κB的DNA结合活性。通过活体显微镜评估肝血窦灌注和白细胞-内皮细胞相互作用。
对乙酰氨基酚导致中度肝血窦灌注衰竭（-15%）以及中性粒细胞浸润，同时伴有核因子-κB和细胞间黏附分子-1以及细胞因子诱导的中性粒细胞趋化因子-1信使核糖核酸的激活。肝细胞和非实质细胞中血红素加氧酶-1信使核糖核酸和蛋白质的诱导（约30倍）与炎症反应平行。用锡原卟啉-IX阻断血红素加氧酶活性可消除对乙酰氨基酚诱导肝脏中性粒细胞积聚和核因子-κB激活，但未能影响肝血窦灌注和肝损伤。
与对乙酰氨基酚肝毒性相关的炎症反应受到血红素加氧酶-1基因平行诱导的调节。然而，在该模型中，血红素加氧酶-1对肝血窦灌注没有允许作用，也不影响肝损伤。这些数据表明，核因子-κB激活和中性粒细胞浸润作为对乙酰氨基酚毒性中肝损伤的持续因素，并不起核心作用。
