Cisplatin Prevents High Mobility Group Box 1 Release and Is Protective in a Murine Model of Hepatic Ischemia/Reperfusion Injury
Cisplatin Prevents High Mobility Group Box 1 Release and Is Protective in a Murine Model of Hepatic Ischemia/Reperfusion Injury
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DOI：
10.1002/hep.23021
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发表时间：
2009-08-01
期刊：
影响因子：
13.5
通讯作者：
Tsung, Allan
中科院分区：
文献类型：
--
作者：
Cardinal, Jon;Pan, Pinhua;Tsung, Allan
核蛋白高迁移率族蛋白1（HMGB 1）是一种重要的炎症介质，参与肝脏缺血再灌注损伤的发病机制。旨在防止其从应激或受损细胞中释放的策略可能有助于预防I/R后的炎症。顺铂是铂化化疗剂的一员，并且可以诱导能够将高迁移率族蛋白保留在细胞核内的DNA损伤。在原代培养的大鼠肝细胞中的体外研究表明，无毒浓度的顺铂可以将HMGB 1隔离在缺氧细胞的细胞核内。类似地，体内施用无毒剂量的顺铂防止与良好建立的肝I/R鼠模型相关的肝损伤，如通过较低的循环血清转氨酶水平、较低的肝脏炎性细胞因子水平（包括肿瘤坏死因子α和白介素-6）、较低的诱导型NO合酶表达和较少的I/R相关的组织病理学变化所测量的。体内作用机制似乎涉及顺铂阻止I/R诱导的HMGB 1释放以及分别以自噬和丝裂原活化蛋白激酶活化的形式改变细胞存活和应激信号传导的能力。结论：低剂量、无毒的顺铂可以在体外将HMGB 1隔离在氧化还原应激的肝细胞核内，并在小鼠肝I/R模型中阻止其体内释放。此外，低剂量顺铂会改变细胞存活和应激信号通路。因此，铂化剂可提供减轻I/R介导的疾病过程的有害作用的新方法。（《肝脏病学》2009年;50：565-574。）
The nuclear protein high mobility group box 1 (HMGB1) is an important inflammatory mediator involved in the pathogenesis of liver ischemia/reperfusion (I/R) injury. Strategies aimed at preventing its release from stressed or damaged cells may be beneficial in preventing inflammation after I/R. Cisplatin is a member of the platinating chemotherapeutic agents and can induce DNA lesions that are capable of retaining high mobility group proteins inside the nucleus of cells. In vitro studies in primary cultured rat hepatocytes show that nontoxic concentrations of cisplatin can sequester HMGB1 inside the nucleus of hypoxic cells. Similarly, the in vivo administration of nontoxic doses of cisplatin prevents liver damage associated with a well-established murine model of hepatic I/R as measured by lower circulating serum aminotransferase levels, lower hepatic inflammatory cytokine levels including tumor necrosis factor a and interleukin-6, lower inducible NO synthase expression, and fewer I/R-associated histopathologic changes. The mechanism of action in vivo appears to involve the capacity of cisplatin to prevent the I/R-induced release of HMGB1 as well as to alter cell survival and stress signaling in the form of autophagy and mitogen-activated protein kinase activation, respectively. Conclusion: Low, nontoxic doses of cisplatin can sequester HMGB1 inside the nucleus of redox-stressed hepatocytes in vitro and prevent its release in vivo in a murine model of hepatic I/R. Furthermore, cell survival and stress signaling pathways are altered by low-dose cisplatin. Therefore, platinating agents may provide a novel approach to mitigating the deleterious effects of I/R-mediated disease processes. (HEPATOLOGY 2009;50:565-574.)