Exaggerated hepatotoxicity of acetaminophen in mice lacking tumor necrosis factor receptor-1 - Potential role of inflammatory mediators
Exaggerated hepatotoxicity of acetaminophen in mice lacking tumor necrosis factor receptor-1 - Potential role of inflammatory mediators
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DOI：
10.1016/s0041-008x(03)00273-4
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发表时间：
2003-10-15
影响因子：
3.8
通讯作者：
Laskin, DL
中科院分区：
文献类型：
--
作者：
Gardner, CR;Laskin, JD;Laskin, DL
利用靶向破坏肿瘤坏死因子受体1 （TNFR1）基因的转基因小鼠，分析了tnf - α在对乙酰氨基酚诱导的促炎性和抗炎介质产生和肝损伤中的作用。对乙酰氨基酚（300 mg/kg）对野生型小鼠造成小叶中心肝坏死。这与肝脏诱导型一氧化氮合酶（NOS II）的表达和硝基酪氨酸染色有关。巨噬细胞趋化蛋白-1 （MCP-1）、KC/gro、白细胞介素-1 β (il -1 β)、基质金属蛋白酶-9 （MMP-9）、结缔组织生长因子（CTGF）、已知参与组织修复的炎症介质以及抗炎细胞因子白细胞介素-10 （IL-10）的表达也在给药后增加。研究发现，TNFR1（-/-）小鼠对对乙酰氨基酚的肝毒性作用明显比野生型小鼠更敏感。这与肝脏中NOS 11的快速和延长的诱导以及硝基酪氨酸染色模式的变化有关。与野生型小鼠相比，对乙酰氨基酚诱导的TNFR1（-/-）小鼠MCP-1、IL- 1 β、CTGF和MMP-9 mRNA的表达也被延迟或降低。相比之下，IL-10的增加更为迅速和明显。这些数据表明，通过TNFR1的信号传导在炎症介质的产生和对乙酰氨基酚诱导的毒性中很重要。(C) 2003 Elsevier Inc.版权所有。
Transgenic mice with a targeted disruption of the tumor necrosis factor receptor 1 (TNFR1) gene were used to analyze the role of TNF-alpha in pro- and anti-inflammatory mediator production and liver injury induced by acetaminophen. Treatment of wild-type mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis. This was correlated with expression of inducible nitric oxide synthase (NOS II) and nitrotyrosine staining of the liver. Expression of macrophage chemotactic protein-1 (MCP-1), KC/gro, interleukin-1beta (IL-1beta), matrix metalloproteinase-9 (MMP-9), and connective tissue growth factor (CTGF), inflammatory mediators known to participate in tissue repair, as well as the anti-inflammatory cytokine, interleukin-10 (IL-10), also increased in the liver following acetaminophen administration. TNFR1(-/-) mice were found to be significantly more sensitive to the hepatotoxic effects of acetaminophen than wild-type mice. This was correlated with more rapid and prolonged induction of NOS 11 in the liver and changes in the pattern of nitrotyrosine staining. Acetaminophen-induced expression of MCP-1, IL- 1beta, CTGF, and MMP-9 mRNA was also delayed or reduced in TNFR1(-/-) mice relative to wild-type mice. In contrast, increases in IL-10 were more rapid and more pronounced. These data demonstrate that signaling through TNFR1 is important in inflammatory mediator production and toxicity induced by acetaminophen. (C) 2003 Elsevier Inc. All rights reserved.