Novel insight into mechanisms of cholestatic liver injury
Novel insight into mechanisms of cholestatic liver injury
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DOI：
10.3748/wjg.v18.i36.4985
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发表时间：
2012-09-28
影响因子：
4.3
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
Woolbright, Benjamin L.;Jaeschke, Hartmut
胆汁淤积导致胆汁酸在血清和肝细胞中积聚。胆汁淤积性肝损伤机制的早期研究强烈暗示胆汁酸诱导的细胞凋亡是肝细胞损伤的主要原因。最近的工作集中在胆汁酸在细胞信号传导中的作用以及无菌炎症在病理生理学中的作用。现代分析方法学的进步使得能够更准确地测量血清、肝脏和胆汁中的胆汁酸浓度，检测水平非常低。有趣的是，毒性胆汁酸水平似乎远低于以前的假设。最初的假设主要基于细胞培养物中的原代肝细胞暴露于μ mol/L浓度的毒性胆汁酸和胆汁盐，体内胆汁酸浓度可能远低于观察到的体外毒性的可能性在损伤机制中具有深远的意义。这篇综述将集中在不同的胆汁酸和不同的胆汁酸浓度如何影响肝细胞在胆汁淤积，并提供洞察这些数据如何支持最近的假设，胆汁淤积性肝损伤可能不会发生通过直接胆汁酸诱导的细胞凋亡，但可能涉及很大程度上炎症细胞介导的肝细胞坏死。(c)2012年百世登。All rights reserved.
Cholestasis results in a buildup of bile acids in serum and in hepatocytes. Early studies into the mechanisms of cholestatic liver injury strongly implicated bile acidinduced apoptosis as the major cause of hepatocellular injury. Recent work has focused both on the role of bile acids in cell signaling as well as the role of sterile inflammation in the pathophysiology. Advances in modern analytical methodology have allowed for more accurate measuring of bile acid concentrations in serum, liver, and bile to very low levels of detection. Interestingly, toxic bile acid levels are seemingly far lower than previously hypothesized. The initial hypothesis has been based largely upon the exposure of mu mol/L concentrations of toxic bile acids and bile salts to primary hepatocytes in cell culture, the possibility that in vivo bile acid concentrations may be far lower than the observed in vitro toxicity has far reaching implications in the mechanism of injury. This review will focus on both how different bile acids and different bile acid concentrations can affect hepatocytes during cholestasis, and additionally provide insight into how these data support recent hypotheses that cholestatic liver injury may not occur through direct bile acid-induced apoptosis, but may involve largely inflammatory cell-mediated liver cell necrosis. (c) 2012 Baishideng. All rights reserved.