Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure.
Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure.
复制标题
DOI：
10.1016/j.fob.2014.08.007
复制
发表时间：
2014
期刊：
影响因子：
2.6
通讯作者：
Asagiri, Masataka
中科院分区：
文献类型：
--
作者：
Takemoto, Kenji;Hatano, Etsuro;Iwaisako, Keiko;Takeiri, Masatoshi;Noma, Naruto;Ohmae, Saori;Toriguchi, Kan;Tanabe, Kazutaka;Tanaka, Hirokazu;Seo, Satoru;Taura, Kojiro;Machida, Keigo;Takeda, Norihiko;Saji, Shigehira;Uemoto, Shinji;Asagiri, Masataka
关键词：
RIPK 依赖性坏死与对乙酰氨基酚 (APAP) 诱导的肝毒性有关。 Necrostatin-1 (Nec-1) 可保护小鼠免受 APAP 诱导的急性肝损伤。 Nec-1 抑制 APAP 诱导的肝细胞中 ROS 的产生。 Nec-1 促进肝细胞对氧化应激的抵抗力。过量使用对乙酰氨基酚（APAP）是急性肝衰竭的最常见原因之一。受损肝脏中各种类型的细胞死亡与 APAP 诱导的肝毒性有关，其中肝细胞坏死性细胞死亡已被证明与疾病发病机制有关。直到最近，坏死还普遍被认为是一种随机且不受调控的细胞死亡形式。然而，最近的研究发现了一种以前未知的程序性坏死形式，称为受体相互作用蛋白激酶 (RIPK) 依赖性坏死（或坏死性凋亡），它由激酶 RIPK1 和 RIPK3 控制。尽管RIPK依赖性坏死与多种疾病状态有关，包括动脉粥样硬化、心肌器官损伤、中风、缺血再灌注损伤、胰腺炎和炎症性肠病。然而，其在 APAP 诱导的肝细胞坏死中的作用仍然难以捉摸。在这里，我们发现 RIPK1 磷酸化是由 APAP 诱导的，RIPK1 磷酸化是 RIPK 依赖性坏死的标志，并且肝脏中 RIPK1 和 RIPK3 的表达模式与 CYP2E1 的表达模式重叠，CYP2E1 在中央静脉区域的活性已被证明对于 APAP 诱导的肝损伤的发生至关重要。此外，RIPK1 抑制剂可改善动物模型中 APAP 诱导的肝毒性，并通过显着抑制肝酶的释放和细胞因子表达水平来强调这一点。 RIPK1 抑制降低了 APAP 损伤的肝细胞中产生的活性氧水平，而 CYP2E1 表达和总谷胱甘肽的消耗率不受影响。值得注意的是，RIPK1 抑制还赋予肝细胞对氧化应激的抵抗力。这些数据共同证明，RIPK 依赖性坏死机制在 APAP 损伤的肝脏中发挥作用，抑制该途径可能有利于 APAP 诱导的暴发性肝衰竭。
RIPK-dependent necrosis is involved in acetaminophen (APAP)-induced hepatotoxicity. Necrostatin-1 (Nec-1) protects mice against APAP-induced acute liver damage. Nec-1 suppresses APAP-induced ROS generation in hepatocytes. Nec-1 promotes resistance to oxidative stress in hepatocytes. Excessive acetaminophen (APAP) use is one of the most common causes of acute liver failure. Various types of cell death in the damaged liver are linked to APAP-induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently, necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed necrosis called receptor-interacting protein kinase (RIPK)-dependent necrosis (or necroptosis), which is controlled by the kinases RIPK1 and RIPK3. Although RIPK-dependent necrosis has been implicated in a variety of disease states, including atherosclerosis, myocardial organ damage, stroke, ischemia–reperfusion injury, pancreatitis, and inflammatory bowel disease. However its involvement in APAP-induced hepatocyte necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK-dependent necrosis, was induced by APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of APAP-induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated APAP-induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic enzymes and cytokine expression levels. RIPK1 inhibition decreased reactive oxygen species levels produced in APAP-injured hepatocytes, whereas CYP2E1 expression and the depletion rate of total glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK-dependent necrotic mechanism operates in the APAP-injured liver and inhibition of this pathway may be beneficial for APAP-induced fulminant hepatic failure.
登录
查看更多内容
影响因子：
5.9
作者：
Jaeschke H;McGill MR;Ramachandran A
通讯作者：
Ramachandran A
影响因子：
4.2
作者：
Figueroa, S;Oset-Gasque, MJ;González, MP
通讯作者：
González, MP
影响因子：
3.8
作者：
Gujral, JS;Knight, TR;Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
13.5
作者：
Kon, K;Kim, JS;Lemasters, JJ
通讯作者：
Lemasters, JJ
影响因子：
3.8
作者：
El-Hassan, H;Anwar, K;Kass, GEN
通讯作者：
Kass, GEN