High-mobility group box 1 exacerbates CCl4-induced acute liver injury in mice
High-mobility group box 1 exacerbates CCl4-induced acute liver injury in mice
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DOI：
10.1016/j.clim.2014.03.021
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发表时间：
2014-07-01
影响因子：
8.6
通讯作者：
Gong, Quan
中科院分区：
文献类型：
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作者：
Chen, Maojian;Huang, Wenjian;Gong, Quan
高迁移率族蛋白1(HMGB1)是一种核因子，一旦释放到细胞外环境也可作为炎症介质。因此，HMGB1已被认为在脓毒症、急性肺损伤、缺血再灌注损伤和1型糖尿病等炎症性疾病中发挥关键作用。然而，其对四氯化碳(CCl4)诱导的肝损伤的影响尚不清楚。在本报告中，我们证明了高水平的HMGB1不仅存在于肝脏坏死区，而且在CCl4攻击后的血清中也存在。与此一致，外源性重组HMGB1可加重CCl4诱导的肝损伤，而HMGB1封闭抗体对CCl4诱导的小鼠急性肝损伤具有保护作用，表现为血清转氨酶的降低和肝组织坏死的减少。机制研究表明，阻断HMGB1可抑制CCl4诱导的丙二醛积累，同时提高超氧化物歧化酶和谷胱甘肽的活性。用HMGB1中和抗体处理小鼠，也显著抑制了促炎介质TNF-α和IL-6的产生，并减弱了HMGB1的表达及其细胞外释放。综上所述，我们的数据表明HMGB1在CCl4诱导的急性肝损伤中起重要作用，而HMGB1中和抗体可以作为预防CCl4诱导的急性肝损伤的有效方案。(C)2014 Elsevier Inc.保留所有权利。
High-mobility group box 1 (HMGB1) is a nuclear factor that can also serve as an imflammatory mediator once released into extracellular milieu. Therefore, HMGB1 has been recognized to play a pivotal role in inflammatory diseases such as sepsis, acute lung injury, ischemia reperfusion injury and type 1 diabetes. Nevertheless, its impact on carbon tetrachloride (CCl4)-induced hepatic injury is yet to be elucidated. In the present report, we demonstrated evidence indicating that high levels of HMGB1 were not only present in the necrotic area of liver but also in the serum after CCl4 challenge. In line with these observations, administration of exogenous recombinant HMGB1 exacerbated CCl4-induced hepatic injury, while HMGB1 blocking antibody provided protection for mice against CCl4-induced acute liver injury as evidenced by the decrease of serum transaminase and reduction of hepatic tissues necrosis. Mechanistic studies revealed that blockade of HMGB1 attenuated CCl4-induced MDA accumulation along with improved SOD and GSH activity. Treatment of mice with HMGB1 neutralizing antibody also significantly inhibited the production of proinflammatory mediators TNF-alpha and IL-6 along with attenuated HMGB1 expression and its extracellular release. Together, our data suggest an essential role for HMGB1 in CCl4-induced acute liver injury, while HMGB1 neutralizing antibody could be served as an effective regimen for preventing CCl4-induced acute liver injury. (C) 2014 Elsevier Inc. All rights reserved.