Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury.
Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury.
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DOI：
10.1016/j.taap.2011.03.001
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发表时间：
2011-05-01
影响因子：
3.8
通讯作者：
Jaeschke H
中科院分区：
文献类型：
--
作者：
Williams CD;Antoine DJ;Shaw PJ;Benson C;Farhood A;Williams DP;Kanneganti TD;Park BK;Jaeschke H
对乙酰氨基酚（APAP）过量是美国和英国急性肝衰竭的主要原因。近年来的研究表明，APAP诱导的损伤部分由白细胞介素-1 β（IL-1β）介导，IL-1β可激活和募集中性粒细胞，加重损伤。成熟的IL-1β由caspase-1形成，依赖于炎性小体活化。本研究的目的是评估Nalp 3炎性体在APAP过量后释放损伤相关分子模式（DAMP）、肝中性粒细胞积聚和肝损伤（ALT，坏死）中的作用。用300 mg/kg APAP处理Nalp 3炎性体的每种组分（半胱天冬酶-1，ASC和NALP 3）缺陷的小鼠24小时;这些小鼠具有与APAP处理的C57 B1/6野生型动物相似的嗜中性粒细胞募集和肝损伤。此外，DAMP（DNA片段、角蛋白-18、低乙酰化和高乙酰化形式的高迁移率族蛋白-1）的血浆水平也类似地升高，野生型和基因敲除小鼠之间无显著差异。此外，阿司匹林治疗，这已被假定为减弱细胞因子的形成和活化的Nalp 3炎性小体后APAP，没有影响释放DAMP，肝中性粒细胞积累或肝损伤。这些数据共同证实了DAMP的释放和APAP过量后的无菌炎症反应。然而，如先前报道的，IL-1β的少量内源性形成和Nalp 3炎性体的活化对APAP肝毒性几乎没有影响。似乎Nalp 3炎性体不是治疗APAP过量的有希望的治疗靶标。
Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US and UK. Recent studies implied that APAP-induced injury is partially mediated by interleukin-1β (IL-1β), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1β is formed by caspase-1, dependent on inflammasome activation. The objective of this investigation was to evaluate the role of the Nalp3 inflammasome on release of damage associated molecular patterns (DAMPs), hepatic neutrophil accumulation and liver injury (ALT, necrosis) after APAP overdose. Mice deficient for each component of the Nalp3 inflammasome (Caspase-1, ASC and NALP3) were treated with 300 mg/kg APAP for 24 h; these mice had similar neutrophil recruitment and liver injury as APAP-treated C57Bl/6 wildtype animals. In addition, plasma levels of DAMPs (DNA fragments, keratin-18, hypo- and hyper-acetylated forms of high mobility group box-1 protein) were similarly elevated with no significant difference between wildtype and gene knockout mice. In addition, aspirin treatment, which has been postulated to attenuate cytokine formation and the activation of the Nalp3 inflammasome after APAP, had no effect on release of DAMPs, hepatic neutrophil accumulation or liver injury. Together these data confirm the release of DAMPs and a sterile inflammatory response after APAP overdose. However, as previously reported minor endogenous formation of IL-1β and the activation of the Nalp3 inflammasome have little impact on APAP hepatotoxicity. It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose.
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