Cell Death Mechanisms and Their Implications in Toxicology
Cell Death Mechanisms and Their Implications in Toxicology
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DOI：
10.1093/toxsci/kfq268
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发表时间：
2011-01-01
影响因子：
3.8
通讯作者：
Zhivotovsky, Boris
中科院分区：
文献类型：
--
作者：
Orrenius, Sten;Nicotera, Pierluigi;Zhivotovsky, Boris
坏死细胞死亡长期以来被认为是化学毒性的最终结果，并且被认为是由于毒性干扰重要细胞功能而导致的简单细胞衰竭。程序性细胞死亡（PCD）或凋亡的新概念的引入极大地改变了这一观点。这一发展已进一步刺激了其他几个遗传PCD模式，如自噬和pyroptosis的表征。与细胞凋亡一样，这些细胞死亡模式由复杂的信号网络控制，其中包含负责它们之间串扰的“开关”。外来化学物质对这些细胞死亡信号网络的招募或抑制可导致急性和慢性毒性。在许多情况下，毒物的这种作用是通过破坏/调节细胞Ca 2+稳态或增加线粒体或其他细胞内区室中活性氧的产生来介导的。半胱天冬酶、钙蛋白酶、溶酶体蛋白酶和核酸内切酶是细胞死亡的主要执行者，并且它们在细胞凋亡的执行阶段经常合作。最后，死亡或垂死的细胞被吞噬细胞识别和吞噬，以防止炎症和相关的组织损伤。有缺陷的巨噬细胞吞噬和细胞尸体的降解也可能是由毒性引起的，并且可能有助于炎症反应和组织稳态的失调。因此，细胞死亡和吞噬调节网络为有毒化学物质提供了许多靶点。
Necrotic cell death was long regarded as the ultimate consequence of chemical toxicity and was thought to result from simple cell failure because of toxic interference with vital cell functions. Introduction of the novel concept of programmed cell death (PCD), or apoptosis, has changed this view dramatically. This development has been further stimulated by the characterization of several other genetically PCD modalities, such as autophagy and pyroptosis. Like apoptosis, these modes of cell death are governed by complex signaling networks, containing "switches" responsible for cross talk between them. Recruitment or repression of these cell death signaling networks by foreign chemicals can lead to acute as well as chronic toxicity. In many instances, such effects of toxicants are mediated by disruption/modulation of cellular Ca2+ homeostasis or increased generation of reactive oxygen species in the mitochondria or other intracellular compartments. Caspases, calpains, lysosomal proteases, and endonucleases are the main executioners of cell death, and they often co-operate during the execution stage of apoptosis. Finally, dead or dying cells are recognized and engulfed by phagocytes to prevent inflammation and associated tissue damage. Defective macrophage engulfment and degradation of cell corpses may also result from toxicity and can contribute to both the inflammatory response and dysregulation of tissue homeostasis. Hence, the cell death and phagocytosis regulatory networks offer a multitude of targets for toxic chemicals.