Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Toxicol Appl Pharmacol. 2010 Sep 15;247(3):169-78. doi: 10.1016/j.taap.2010.07.004. Epub 2010 Jul 15.
Acetaminophen (APAP) overdose can result in serious liver injury and potentially death. Toxicity is dependent on metabolism of APAP to a reactive metabolite initiating a cascade of intracellular events resulting in hepatocellular necrosis. This early injury triggers a sterile inflammatory response with formation of cytokines and innate immune cell infiltration in the liver. Recently, IL-1beta signaling has been implicated in the potentiation of APAP-induced liver injury. To test if IL-1beta formation through caspase-1 is critical for the pathophysiology, C57Bl/6 mice were treated with the pan-caspase inhibitor Z-VD-fmk to block the inflammasome-mediated maturation of IL-1beta during APAP overdose (300 mg/kg APAP). This intervention did not affect IL-1beta gene transcription but prevented the increase in IL-1beta plasma levels. However, APAP-induced liver injury and neutrophil infiltration were not affected. Similarly, liver injury and the hepatic neutrophilic inflammation were not attenuated in IL-1-receptor-1 deficient mice compared to wild-type animals. To evaluate the potential of IL-1beta to increase injury, mice were given pharmacological doses of IL-1beta after APAP overdose. Despite increased systemic activation of neutrophils and recruitment into the liver, there was no alteration in injury. We conclude that endogenous IL-1beta formation after APAP overdose is insufficient to activate and recruit neutrophils into the liver or cause liver injury. Even high pharmacological doses of IL-1beta, which induce hepatic neutrophil accumulation and activation, do not enhance APAP-induced liver injury. Thus, IL-1 signaling is irrelevant for APAP hepatotoxicity. The inflammatory cascade is a less important therapeutic target than intracellular signaling pathways to attenuate APAP-induced liver injury.
对乙酰氨基酚（APAP）过量可导致严重肝损伤，甚至可能导致死亡。毒性取决于 APAP 的代谢产物，该产物转化为活性代谢物，引发细胞内一系列事件，导致肝细胞坏死。这种早期损伤会引发无菌性炎症反应，导致细胞因子形成和固有免疫细胞浸润肝脏。最近，IL-1β信号转导被认为在增强 APAP 诱导的肝损伤中起作用。为了验证 caspase-1 介导的 IL-1β形成是否对肝损伤的病理生理学至关重要，用广谱半胱天冬酶抑制剂 Z-VD-fmk 预处理 C57Bl/6 小鼠，以阻断 APAP 过量时（300mg/kg APAP）炎症小体介导的 IL-1β成熟。该干预措施不影响 IL-1β基因转录，但可防止 IL-1β血浆水平升高。然而，APAP 诱导的肝损伤和中性粒细胞浸润不受影响。同样，与野生型动物相比，IL-1 受体 1 缺陷型小鼠的肝损伤和肝中性粒细胞炎症也没有减轻。为了评估 IL-1β增加损伤的可能性，在 APAP 过量后给予小鼠药理剂量的 IL-1β。尽管系统中性粒细胞激活增加并募集到肝脏，但损伤没有改变。我们的结论是，APAP 过量后内源性 IL-1β的形成不足以激活并募集中性粒细胞进入肝脏或引起肝损伤。即使是高剂量的 IL-1β，诱导肝中性粒细胞聚集和激活，也不会增强 APAP 诱导的肝损伤。因此，IL-1 信号对 APAP 肝毒性并不重要。炎症级联反应是减轻 APAP 诱导的肝损伤的治疗靶点，其重要性不如细胞内信号通路。
