期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 247, 期 3, 页码 169-178出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2010.07.004
关键词
Acetaminophen; Hepatotoxicity; Interleukin-1; Inflammasome; Neutrophils; Inflammation
资金
- National Institutes of Health [R01 DK070195, R01 AA12916]
- National Center for Research Resources (NCRR), National Institutes of Health [P20 RR016475, P20 RR021940]
- National Institute of Environmental Health Sciences [T32 ES007079-26A2]
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-1 beta signaling has been implicated in the potentiation of APAP-induced liver injury. To test if IL-1 beta formation through caspase-1 is critical for the pathophysiology, C57BI/6 mice were treated with the pan-caspase inhibitor Z-VD-fmk to block the inflammasome-mediated maturation of IL-1 beta during APAP overdose (300 mg/kg APAP). This intervention did not affect IL-1 beta gene transcription but prevented the increase in IL-1 beta 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-1 beta to increase injury, mice were given pharmacological doses of IL-1 beta 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-1 beta formation after APAP overdose is insufficient to activate and recruit neutrophils into the liver or cause liver injury. Even high pharmacological doses of IL-1 beta, 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. (C) 2010 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据