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Mechanisms and pathophysiological significance of sterile inflammation during acetaminophen hepatotoxicity
Food and Chemical Toxicology ( IF 3.9 ) Pub Date : 2020-03-04 , DOI: 10.1016/j.fct.2020.111240
Hartmut Jaeschke 1 , Anup Ramachandran 1
Affiliation  

Acetaminophen (APAP) is a widely used analgesic drug, which can cause severe liver injury after an overdose. The intracellular signaling mechanisms of APAP-induced cell death such as reactive metabolite formation, mitochondrial dysfunction and nuclear DNA fragmentation have been extensively studied. Hepatocyte necrosis releases damage-associated molecular patterns (DAMPs) which activate cytokine and chemokine formation in macrophages. These signals activate and recruit neutrophils, monocytes and other leukocytes into the liver. While this sterile inflammatory response removes necrotic cell debris and promotes tissue repair, the capability of leukocytes to also cause tissue injury makes this a controversial topic. This review summarizes the literature on the role of various DAMPs, cytokines and chemokines, and the pathophysiological function of Kupffer cells, neutrophils, monocytes and monocyte-derived macrophages, and NK and NKT cells during APAP hepatotoxicity. Careful evaluation of results and experimental designs of studies dealing with the inflammatory response after APAP toxicity provide very limited evidence for aggravation of liver injury but support of the hypothesis that these leukocytes promote tissue repair. In addition, many cytokines and chemokines modulate tissue injury by affecting the intracellular signaling events of cell death rather than toxicity of leukocytes. Reasons for the controversial results in this area are also discussed.



中文翻译:

对乙酰氨基酚肝毒性过程中无菌性炎症的机制及病理生理意义

对乙酰氨基酚 (APAP) 是一种广泛使用的镇痛药物,过量服用会导致严重的肝损伤。APAP 诱导的细胞死亡的细胞内信号传导机制,如反应性代谢物形成、线粒体功能障碍和核 DNA 断裂已被广泛研究。肝细胞坏死释放损伤相关分子模式 (DAMP),激活巨噬细胞中的细胞因子和趋化因子形成。这些信号激活并招募中性粒细胞、单核细胞和其他白细胞进入肝脏。虽然这种无菌炎症反应可以去除坏死细胞碎片并促进组织修复,但白细胞也能引起组织损伤的能力使其成为一个有争议的话题。这篇综述总结了关于各种 DAMP、细胞因子和趋化因子作用的文献,以及 APAP 肝毒性过程中 Kupffer 细胞、中性粒细胞、单核细胞和单核细胞衍生的巨噬细胞以及 NK 和 NKT 细胞的病理生理功能。仔细评估处理 APAP 毒性后炎症反应的研究结果和实验设计为肝损伤加重提供了非常有限的证据,但支持这些白细胞促进组织修复的假设。此外,许多细胞因子和趋化因子通过影响细胞死亡的细胞内信号传导事件而不是白细胞的毒性来调节组织损伤。还讨论了该领域有争议的结果的原因。仔细评估处理 APAP 毒性后炎症反应的研究结果和实验设计为肝损伤加重提供了非常有限的证据,但支持这些白细胞促进组织修复的假设。此外,许多细胞因子和趋化因子通过影响细胞死亡的细胞内信号传导事件而不是白细胞的毒性来调节组织损伤。还讨论了该领域有争议的结果的原因。仔细评估处理 APAP 毒性后炎症反应的研究结果和实验设计为肝损伤加重提供了非常有限的证据,但支持这些白细胞促进组织修复的假设。此外,许多细胞因子和趋化因子通过影响细胞死亡的细胞内信号传导事件而不是白细胞的毒性来调节组织损伤。还讨论了该领域有争议的结果的原因。

更新日期:2020-03-04
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