Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice
Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice
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DOI：
10.1021/tx0255976
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发表时间：
2002-12-01
影响因子：
4.1
通讯作者：
Pohl, LR
中科院分区：
文献类型：
--
作者：
Ju, C;Reilly, TP;Pohl, LR
包括对乙酰氨基酚（APAP）在内的各种有毒物质所诱导的肝损伤，在一定程度上归因于肝脏内常驻的枯否细胞产生促炎细胞因子和其他介质。然而，我们实验室最近的证据表明，肝保护因子，如白细胞介素（IL）-10和环氧化酶衍生的介质，在肝脏受损时也会上调，以帮助防止损伤加剧，并且枯否细胞被认为是这些调节因子的一个来源。在其他模型中，枯否细胞在肝脏的病理生理状态下也具有重要的调节功能。因此，我们使用脂质体包裹的氯膦酸盐（脂质体/氯膦酸盐）作为一种有效的枯否细胞清除剂，在对乙酰氨基酚诱导的小鼠肝损伤模型中重新评估了枯否细胞的作用。我们发现，与之前报道的用一种广泛使用的巨噬细胞抑制剂氯化钆预处理小鼠的情况相反，氯化钆不会清除枯否细胞，但能适度保护小鼠免受对乙酰氨基酚诱导的肝毒性，而静脉注射脂质体/氯膦酸盐会导致枯否细胞几乎完全被清除，与用空脂质体预处理的小鼠相比，对APAP诱导的肝损伤的易感性显著增加。这种易感性的增加显然与APAP的代谢无关，因为脂质体/氯膦酸盐预处理不会改变APAP - 蛋白质加合物的水平。相反，脂质体/氯膦酸盐清除枯否细胞导致几种肝脏调节细胞因子和介质的肝脏mRNA表达水平显著下降，包括IL - 6、IL - 10、IL - 18结合蛋白和补体1q，这表明在该模型中枯否细胞是这些介质产生的一个重要来源。我们的研究结果表明，除了其原毒性作用外，枯否细胞还可以通过产生多种调节因子在肝脏中发挥重要的保护作用，这些调节因子可能抵消炎症反应和/或刺激肝脏再生。
Hepatic injury induced by various toxic agents, including acetaminophen (APAP), has been attributed, in part, to the production of proinflammatory cytokines and other mediators by resident Kupffer cells within the liver. However, recent evidence from our laboratory has demonstrated that hepato-protective factors, such as interleukin (IL)-10 and cyclooxygenase-derived mediators, are also upregulated in response to hepatic damage to help protect against exacerbated injury, and Kupffer cells have been suggested to be a source of these modulatory factors. In other models, Kupffer cells also serve important regulatory functions in pathophysiological states of the liver. Therefore, we reevaluated the role of Kupffer cells in a murine model of APAP-induced liver injury using liposome-entrapped clodronate (liposome/clodronate) as an effective Kupffer cell-depleting agent. We show that in contrast to pretreatment of mice with a widely used macrophage inhibitor, gadolinium chloride, which did not deplete Kupffer cells but moderately protected against APAP-induced hepatotoxicity as reported previously, the intravenous injection of liposome/clodronate caused nearly complete elimination of Kupffer cells and significantly increased susceptibility to A-PAP-induced liver injury as compared with mice pretreated with empty liposomes. This increased susceptibility was apparently unrelated to the metabolism of APAP since liposome/clodronate pretreatment did not alter APAP-protein adduct levels. Instead, Kupffer cell depletion by liposome/clodronate led to significant decreases in the levels of hepatic mRNA expression of several hepato-regulatory cytokines and mediators, including IL-6, IL-10, IL-18 binding protein and complement 1q, suggesting that Kupffer cells are a significant source for production of these mediators in this model. Our findings indicate that, in addition to their protoxicant activities, Kupffer cells can also have an important protective function in the liver through the production of a variety of modulatory factors which may counteract inflammatory responses and/or stimulate liver regeneration.