Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity
Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity
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DOI：
10.1016/j.taap.2006.04.010
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发表时间：
2006-10-01
影响因子：
3.8
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
Cover, Cathleen;Liu, Jie;Jaeschke, Hartmut
对乙酰氨基酚（AAP）过量后，中性粒细胞被募集到肝脏中，但这种急性炎症反应的病理生理学相关性仍不清楚。为了解决这个问题，我们比较了C3 Heb/FeJ和C57 BL/6小鼠用300 mg/kg AAP治疗后长达24 h的肝损伤、肝中性粒细胞蓄积和炎症基因mRNA表达的时间过程。虽然在肝损伤方面没有相关差异（通过血浆丙氨酸氨基转移酶活性和坏死面积的增加来评估），但中性粒细胞的数量和几种促炎基因的表达（例如，肿瘤坏死因子-α、白细胞介素-1 β和巨噬细胞炎性蛋白-2）在C3 Heb/FeJ小鼠中高于C57 BL/6小鼠。相反，C57 BL/6小鼠中抗炎基因白细胞介素-10和血红素加氧酶-1的表达更高。尽管大量的肝中性粒细胞积累，没有一个肝脏切片从两个菌株染色阳性次氯酸盐修饰的蛋白质，一个特定的标记物嗜中性粒细胞诱导的氧化应激。此外，治疗与NADPH氧化酶抑制剂diphenyleneiodonium，氯化物或夹竹桃麻素或抗中性粒细胞抗体Gr-1没有保护AAP肝毒性。此外，虽然细胞间粘附分子-1（ICAM-1）以前被证明是重要的中性粒细胞外渗和组织损伤在几个模型中，ICAM-1缺陷的小鼠不能保护AAP介导的肝损伤。总之，这些数据不支持中性粒细胞加重AAP过量诱导的肝损伤的假设。(c)2006爱思唯尔公司All rights reserved.
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-alpha, interleukin-1 beta and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interieukin-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. (c) 2006 Elsevier Inc. All rights reserved.