Malhi Harmeet, Gores Gregory J, Lemasters John J
Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
Hepatology. 2006 Feb;43(2 Suppl 1):S31-44. doi: 10.1002/hep.21062.
Death of hepatocytes and other hepatic cell types is a characteristic feature of liver diseases as diverse as cholestasis, viral hepatitis, ischemia/reperfusion, liver preservation for transplantation and drug/toxicant-induced injury. Cell death typically follows one of two patterns: oncotic necrosis and apoptosis. Necrosis is typically the consequence of acute metabolic perturbation with ATP depletion as occurs in ischemia/reperfusion and acute drug-induced hepatotoxicity. Apoptosis, in contrast, represents the execution of an ATP-dependent death program often initiated by death ligand/death receptor interactions, such as Fas ligand with Fas, which leads to a caspase activation cascade. A common event leading to both apoptosis and necrosis is mitochondrial permeabilization and dysfunction, although the mechanistic basis of mitochondrial injury may vary in different settings. Prevention of these modes of cell death is an important target of therapy, but controversies still exist regarding which mode of cell death predominates in various forms of liver disease and injury. Resolution of these controversies may come with the recognition that apoptosis and necrosis frequently represent alternate outcomes of the same cellular pathways to cell death, especially for cell death mediated by mitochondrial permeabilization. An understanding of processes leading to liver cell death will be important for development of effective interventions to prevent hepatocellular death leading to liver failure and to promote cancer and stellate cell death in malignancy and fibrotic disease.
肝细胞和其他肝细胞类型的死亡是多种肝脏疾病的特征性表现，这些疾病包括胆汁淤积、病毒性肝炎、缺血/再灌注、肝移植保存以及药物/毒物诱导的损伤。细胞死亡通常遵循两种模式之一：胀亡性坏死和凋亡。坏死通常是急性代谢紊乱导致ATP耗竭的结果，如在缺血/再灌注和急性药物性肝毒性中发生的情况。相比之下，凋亡代表了一个依赖ATP的死亡程序的执行，该程序通常由死亡配体/死亡受体相互作用启动，如Fas配体与Fas的相互作用，这会导致半胱天冬酶激活级联反应。导致凋亡和坏死的一个共同事件是线粒体通透性改变和功能障碍，尽管线粒体损伤的机制基础在不同情况下可能有所不同。预防这些细胞死亡模式是治疗的一个重要靶点，但关于哪种细胞死亡模式在各种形式的肝脏疾病和损伤中占主导地位仍存在争议。认识到凋亡和坏死常常代表同一细胞死亡途径的不同结果，尤其是对于由线粒体通透性改变介导的细胞死亡，可能有助于解决这些争议。了解导致肝细胞死亡的过程对于开发有效的干预措施至关重要，这些干预措施可预防导致肝衰竭的肝细胞死亡，并促进恶性肿瘤和纤维化疾病中的癌细胞和星状细胞死亡。
