AlWahsh Mohammad, Othman Amnah, Hamadneh Lama, Telfah Ahmad, Lambert Jörg, Hikmat Suhair, Alassi Amin, Mohamed Fatma El Zahraa, Hergenröder Roland, Al-Qirim Tariq, Dooley Steven, Hammad Seddik
Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan.
Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Bunsen-Kirchhoff-Straße 11, 44139 Dortmund, Germany.
EXCLI J. 2019 Feb 6;18:51-62. eCollection 2019.
Repeated administration of hepatotoxicants is usually accompanied by liver fibrosis. However, the difference in response as a result of repeated exposures of acetaminophen (APAP) compared to a single dose is not well-studied. Therefore, in the current study, the liver response after a second dose of APAP was investigated. Adult fasted Balb/C mice were exposed to two toxic doses of 300 mg/kg APAP, which were administered 72 h apart from each other. Subsequently, blood and liver from the treated mice were collected 24 h and 72 h after both APAP administrations. Liver transaminase, i.e. alanine amino transferase (ALT) and aspartate amino transferase (AST) levels revealed that the fulminant liver damage was reduced after the second APAP administration compared to that observed at the same time point after the first treatment. These results correlated with the necrotic areas as indicated by histological analyses. Surprisingly, Picro Sirius Red (PSR) staining showed that the accumulation of extracellular matrix after the second dose coincides with the upregulation of some fibrogenic signatures, e.g., alpha smooth muscle actin. Non-targeted liver tissue metabolic profiling indicates that most alterations occur 24 h after the first dose of APAP. However, the levels of most metabolites recover to basal values over time. This organ adaptation process is also confirmed by the upregulation of antioxidative systems like e.g. superoxide dismutase and catalase. From the results, it can be concluded that there is a different response of the liver to APAP toxic doses, if the liver has already been exposed to APAP. A necroinflammatory process followed by a liver regeneration was observed after the first APAP exposure. However, fibrogenesis through the accumulation of extracellular matrix is observed after a second challenge. Therefore, further studies are required to mechanistically understand the so called "liver memory".
反复给予肝毒性物质通常会伴随肝纤维化。然而，与单次给药相比，对乙酰氨基酚（APAP）反复暴露后的反应差异尚未得到充分研究。因此，在本研究中，对第二次给予APAP后的肝脏反应进行了调查。成年禁食的Balb/C小鼠接受了两次300 mg/kg APAP的毒性剂量，两次给药间隔72小时。随后，在两次APAP给药后24小时和72小时收集处理后小鼠的血液和肝脏。肝转氨酶，即丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平显示，与第一次治疗后相同时间点相比，第二次给予APAP后暴发性肝损伤有所减轻。这些结果与组织学分析所示的坏死区域相关。令人惊讶的是，苦味酸天狼星红（PSR）染色显示，第二次给药后细胞外基质的积累与一些纤维化标志物（如α平滑肌肌动蛋白）的上调同时出现。非靶向肝脏组织代谢谱分析表明，大多数变化发生在第一次给予APAP后24小时。然而，随着时间的推移，大多数代谢物水平恢复到基础值。抗氧化系统（如超氧化物歧化酶和过氧化氢酶）的上调也证实了这种器官适应过程。从结果可以得出结论，如果肝脏已经暴露于APAP，肝脏对APAP毒性剂量的反应会有所不同。第一次APAP暴露后观察到坏死性炎症过程，随后是肝脏再生。然而，第二次攻击后观察到通过细胞外基质积累的纤维化形成。因此，需要进一步研究从机制上理解所谓的“肝脏记忆”。
