The hepatic inflammatory response after acetaminophen overdose: Role of neutrophils
The hepatic inflammatory response after acetaminophen overdose: Role of neutrophils
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DOI：
10.1093/toxsci/54.2.509
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发表时间：
2000-04-01
影响因子：
3.8
通讯作者：
Jaeschke, H
中科院分区：
文献类型：
--
作者：
Lawson, JA;Farhood, A;Jaeschke, H
对乙酰氨基酚过量会导致严重的肝损伤和肝功能衰竭。有证据表明，炎症细胞可能参与病理生理学。因此，本研究的目的是表征用300 mg/kg对乙酰氨基酚处理C3 Heb/FeJ小鼠后的嗜中性粒细胞炎症反应。一项时程研究表明，中性粒细胞在肝损伤发生后平行或轻微蓄积在肝损伤发生后。与基线水平（7 +/- 1）相比，肝脏中的中性粒细胞数量较多（12 h时209 +/- 64 PMN/50高倍视野）。在损伤过程中，TNF-α和C-X-C趋化因子KC和MIP-2的血清水平分别比对照组增加了28倍、14倍和295倍。此外，MIP-2和KC的mRNA表达上调对乙酰氨基酚处理的动物的肝脏中的核糖核酸酶保护测定，但是，没有这些介质产生足够大的量来解释中性粒细胞在肝脏中的隔离。在循环中性粒细胞上没有Mac-1（CD 11b/CD 18）的上调或L-选择素的脱落。此外，抗CD 18抗体在前24小时内对对乙酰氨基酚过量没有保护作用。这些结果表明，在对乙酰氨基酚过量后存在局部炎症反应，包括中性粒细胞在肝脏中的大量积累。由于β 2整合素对中性粒细胞的细胞毒性至关重要，这些结果表明中性粒细胞对AAP诱导的肝脏的启动或进展没有贡献。对乙酰氨基酚过量后观察到的炎症可能是足以招募中性粒细胞以清除坏死细胞的反应的特征，但不足以引起额外的损伤。
Acetaminophen overdose induces severe liver injury and hepatic failure. There is evidence that inflammatory cells may be involved in the pathophysiology. Thus, the aim of this investigation was to characterize the neutrophilic inflammatory response after treatment of C3Heb/FeJ mice with 300 mg/kg acetaminophen, A time course study showed that neutrophils accumulate in the liver parallel to or slightly after the development of liver injury. The number of neutrophils in the liver was substantial (209 +/- 64 PMN/50 high-power fields at 12 h) compared to baseline levels (7 +/- 1). Serum levels of TNF-alpha and the C-X-C chemokines KC and MIP-2 increased by 28-, 14-, and 295-fold, respectively, over levels found in controls during the injury process. In addition, mRNA expression of MIP-2 and KC were upregulated in livers of acetaminophen-treated animals as determined by ribonuclease protection assay, However, none of these mediators were generated in large enough quantities to account for neutrophil sequestration in the liver. There was no upregulation of Mac-1 (CD11b/ CD18) or shedding of L-selectin on circulating neutrophils, Moreover, an anti-CD18 antibody had no protective effect against acetaminophen overdose during the first 24 h, These results indicate that there is a local inflammatory response after acetaminophen overdose, including a substantial accumulation of neutrophils in the liver. Because of the critical importance of beta(2) integrins for neutrophil cytotoxicity, these results suggest that neutrophils do not contribute to the initiation or progression of AAP-induced liver. The inflammation observed after acetaminophen overdose may be characteristic for a response sufficient to recruit neutrophils for the purpose of removing necrotic cells but is not severe enough to cause additional damage.