Khan Hilal Ahmad, Ahmad Muhammad Zishan, Khan Junaid Ali, Arshad Muhammad Imran
Institute of Microbiology, University of Agriculture, Faisalabad 38040, Pakistan.
Hepatobiliary Pancreat Dis Int. 2017 Jun;16(3):245-256. doi: 10.1016/s1499-3872(17)60014-6.
Liver inflammation or hepatitis is a result of pluripotent interactions of cell death molecules, cytokines, chemokines and the resident immune cells collectively called as microenvironment. The interplay of these inflammatory mediators and switching of immune responses during hepatotoxic, viral, drug-induced and immune cell-mediated hepatitis decide the fate of liver pathology. The present review aimed to describe the mechanisms of liver injury, its relevance to human liver pathology and insights for the future therapeutic interventions.
The data of mouse hepatic models and relevant human liver diseases presented in this review are systematically collected from PubMed, ScienceDirect and the Web of Science databases published in English.
The hepatotoxic liver injury in mice induced by the metabolites of CCl, acetaminophen or alcohol represent necrotic cell death with activation of cytochrome pathway, formation of reactive oxygen species (ROS) and mitochondrial damage. The Fas or TNF-alpha induced apoptotic liver injury was dependent on activation of caspases, release of cytochrome c and apoptosome formation. The ConA-hepatitis demonstrated the involvement of TRAIL-dependent necrotic/necroptotic cell death with activation of RIPK1/3. The alpha-GalCer-induced liver injury was mediated by TNF-alpha. The LPS-induced hepatitis involved TNF-alpha, Fas/FasL, and perforin/granzyme cell death pathways. The MHV3 or Poly(I:C) induced liver injury was mediated by natural killer cells and TNF-alpha signaling. The necrotic ischemia-reperfusion liver injury was mediated by hypoxia, ROS, and pro-inflammatory cytokines; however, necroptotic cell death was found in partial hepatectomy. The crucial role of immune cells and cell death mediators in viral hepatitis (HBV, HCV), drug-induced liver injury, non-alcoholic fatty liver disease and alcoholic liver disease in human were discussed.
The mouse animal models of hepatitis provide a parallel approach for the study of human liver pathology. Blocking or stimulating the pathways associated with liver cell death could unveil the novel therapeutic strategies in the management of liver diseases.
肝脏炎症或肝炎是细胞死亡分子、细胞因子、趋化因子以及统称为微环境的驻留免疫细胞之间多能相互作用的结果。这些炎症介质之间的相互作用以及在肝毒性、病毒性、药物性和免疫细胞介导的肝炎过程中免疫反应的转换决定了肝脏病理的转归。本综述旨在描述肝损伤的机制、其与人类肝脏病理的相关性以及对未来治疗干预的见解。
本综述中呈现的小鼠肝脏模型和相关人类肝脏疾病的数据是从以英文发表的PubMed、ScienceDirect和科学引文索引数据库中系统收集的。
由四氯化碳、对乙酰氨基酚或酒精的代谢产物诱导的小鼠肝毒性肝损伤表现为坏死性细胞死亡，伴有细胞色素途径激活、活性氧（ROS）形成和线粒体损伤。Fas或肿瘤坏死因子-α（TNF-α）诱导的凋亡性肝损伤依赖于半胱天冬酶的激活、细胞色素c的释放和凋亡小体的形成。刀豆蛋白A诱导的肝炎表明肿瘤坏死因子相关凋亡诱导配体（TRAIL）依赖性坏死性 / 坏死性凋亡细胞死亡与受体相互作用蛋白激酶1/3（RIPK1/3）的激活有关。α-半乳糖神经酰胺诱导的肝损伤由TNF-α介导。脂多糖（LPS）诱导的肝炎涉及TNF-α、Fas/FasL和穿孔素/颗粒酶细胞死亡途径。小鼠肝炎病毒3型（MHV3）或聚肌苷酸:聚胞苷酸（Poly(I:C)）诱导的肝损伤由自然杀伤细胞和TNF-α信号传导介导。坏死性缺血再灌注肝损伤由缺氧、ROS和促炎细胞因子介导；然而，在部分肝切除术中发现了坏死性凋亡细胞死亡。讨论了免疫细胞和细胞死亡介质在人类病毒性肝炎（乙肝病毒、丙肝病毒）、药物性肝损伤、非酒精性脂肪性肝病和酒精性肝病中的关键作用。
小鼠肝炎动物模型为研究人类肝脏病理提供了一种平行方法。阻断或刺激与肝细胞死亡相关的途径可能揭示肝脏疾病管理中的新治疗策略。
