Hartmut Jaeschke, David S Umbaugh, Anup Ramachandran
{"title":"对乙酰氨基酚诱导的肝毒性中的热蛋白沉积作用","authors":"Hartmut Jaeschke, David S Umbaugh, Anup Ramachandran","doi":"10.3390/livers2040032","DOIUrl":null,"url":null,"abstract":"<p><p>Acetaminophen (APAP) is a widely used pain reliever that can cause liver injury or liver failure in response to an overdose. Understanding the mechanisms of APAP-induced cell death is critical for identifying new therapeutic targets. In this respect it was hypothesized that hepatocytes die by oncotic necrosis, apoptosis, necroptosis, ferroptosis and more recently pyroptosis. The latter cell death is characterized by caspase-dependent gasdermin cleavage into a C-terminal and an N-terminal fragment, which forms pores in the plasma membrane. The gasdermin pores can release potassium, interleukin-1β (IL-1β), IL-18, and other small molecules in a sublytic phase, which can be the main function of the pores in certain cell types such as inflammatory cells. Alternatively, the process can progress to full lysis of the cell (pyroptosis) with extensive cell contents release. This review discusses the experimental evidence for the involvement of pyroptosis in APAP hepatotoxicity as well as the arguments against pyroptosis as a relevant mechanism of APAP-induced cell death in hepatocytes. Based on the critical evaluation of the currently available literature and understanding of the pathophysiology, it can be concluded that pyroptotic cell death is unlikely to be a relevant contributor to APAP-induced liver injury.</p>","PeriodicalId":74083,"journal":{"name":"Livers","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9802630/pdf/","citationCount":"0","resultStr":"{\"title\":\"Role of Pyroptosis in Acetaminophen-Induced Hepatotoxicity.\",\"authors\":\"Hartmut Jaeschke, David S Umbaugh, Anup Ramachandran\",\"doi\":\"10.3390/livers2040032\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Acetaminophen (APAP) is a widely used pain reliever that can cause liver injury or liver failure in response to an overdose. Understanding the mechanisms of APAP-induced cell death is critical for identifying new therapeutic targets. In this respect it was hypothesized that hepatocytes die by oncotic necrosis, apoptosis, necroptosis, ferroptosis and more recently pyroptosis. The latter cell death is characterized by caspase-dependent gasdermin cleavage into a C-terminal and an N-terminal fragment, which forms pores in the plasma membrane. The gasdermin pores can release potassium, interleukin-1β (IL-1β), IL-18, and other small molecules in a sublytic phase, which can be the main function of the pores in certain cell types such as inflammatory cells. Alternatively, the process can progress to full lysis of the cell (pyroptosis) with extensive cell contents release. This review discusses the experimental evidence for the involvement of pyroptosis in APAP hepatotoxicity as well as the arguments against pyroptosis as a relevant mechanism of APAP-induced cell death in hepatocytes. Based on the critical evaluation of the currently available literature and understanding of the pathophysiology, it can be concluded that pyroptotic cell death is unlikely to be a relevant contributor to APAP-induced liver injury.</p>\",\"PeriodicalId\":74083,\"journal\":{\"name\":\"Livers\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2022-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9802630/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Livers\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.3390/livers2040032\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2022/12/13 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Livers","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3390/livers2040032","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/12/13 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
对乙酰氨基酚(APAP)是一种广泛使用的止痛药,过量服用可导致肝损伤或肝衰竭。了解 APAP 诱导细胞死亡的机制对于确定新的治疗靶点至关重要。在这方面,有人假设肝细胞会通过肿瘤性坏死、凋亡、坏死凋亡、铁凋亡以及最近的热凋亡而死亡。后一种细胞死亡的特点是依赖于 Caspase 的 gasdermin 分裂成 C 端和 N 端片段,并在质膜上形成孔。气孔可在亚溶解阶段释放钾、白细胞介素-1β(IL-1β)、IL-18 和其他小分子,这可能是气孔在某些细胞类型(如炎症细胞)中的主要功能。另外,这一过程也可能发展为细胞的完全裂解(热解),并释放出大量细胞内容物。本综述讨论了参与 APAP 肝毒性的裂解过程的实验证据,以及反对将裂解作为 APAP 诱导肝细胞死亡的相关机制的论据。根据对现有文献的批判性评估和对病理生理学的理解,可以得出结论:热昏迷细胞死亡不太可能是 APAP 诱导肝损伤的相关因素。
Role of Pyroptosis in Acetaminophen-Induced Hepatotoxicity.
Acetaminophen (APAP) is a widely used pain reliever that can cause liver injury or liver failure in response to an overdose. Understanding the mechanisms of APAP-induced cell death is critical for identifying new therapeutic targets. In this respect it was hypothesized that hepatocytes die by oncotic necrosis, apoptosis, necroptosis, ferroptosis and more recently pyroptosis. The latter cell death is characterized by caspase-dependent gasdermin cleavage into a C-terminal and an N-terminal fragment, which forms pores in the plasma membrane. The gasdermin pores can release potassium, interleukin-1β (IL-1β), IL-18, and other small molecules in a sublytic phase, which can be the main function of the pores in certain cell types such as inflammatory cells. Alternatively, the process can progress to full lysis of the cell (pyroptosis) with extensive cell contents release. This review discusses the experimental evidence for the involvement of pyroptosis in APAP hepatotoxicity as well as the arguments against pyroptosis as a relevant mechanism of APAP-induced cell death in hepatocytes. Based on the critical evaluation of the currently available literature and understanding of the pathophysiology, it can be concluded that pyroptotic cell death is unlikely to be a relevant contributor to APAP-induced liver injury.