Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
Department of Health Sciences, University of East Piedmont (UPO), Novara, Italy.
Clin Sci (Lond). 2018 Mar 15;132(5):609-613. doi: 10.1042/CS20171313.
Drug-induced liver injury (DILI) remains a clinical challenge due to the poorly predictable outcomes. Accordingly, considerable efforts have been devoted to unravel the risk factors responsible for DILI worsening toward acute liver failure (ALF), liver transplantation (LT), and/or death. From a pathogenic point of view, exhaustion of drug metabolizing pathways, cell death mechanisms, activation of local immune cells, such as Kupffer cells, and recruitment of inflammatory leukocytes including monocytes and lymphocytes are key drivers of DILI progression. Taking into account that the liver is a sexually dimorphic organ, in the recent past several studies aimed to investigate the implications of gender differences in promoting DILI. While sex discrepancies in DILI include the hepatic drug metabolism or direct effects of steroid hormones (e.g. androgens and estrogens) on signaling pathways in the liver, relatively little is known on gender differences in modulating liver innate immune responses. In a previous issue of , Bizzaro and co-workers, analyzed sex-dependent differences in experimental acute liver injury and regeneration in mice. The authors observed a time-delay in the recovery process in male animals associated with a higher recruitment of monocytes expressing the androgen receptor (AR) as compared with females. Treatment of male mice with the pharmacological AR antagonist flutamide reduced monocyte recruitment in mice. Likewise, human male patients suffering from DILI displayed higher circulating immature and potentially more inflammatory monocytes. Altogether, these observations provide new insights into sex-dependent immune mechanisms in the context of acute liver injury, suggesting gender disparate inflammatory and regenerative responses following DILI.
药物性肝损伤（DILI）仍然是一个临床挑战，因为其结局难以预测。因此，人们做出了相当大的努力来揭示导致 DILI 向急性肝衰竭（ALF）、肝移植（LT）和/或死亡恶化的风险因素。从发病机制的角度来看，药物代谢途径的耗竭、细胞死亡机制、局部免疫细胞（如库普弗细胞）的激活以及包括单核细胞和淋巴细胞在内的炎症白细胞的募集是 DILI 进展的关键驱动因素。考虑到肝脏是一个性别二态器官，最近有几项研究旨在研究性别差异在促进 DILI 中的作用。虽然 DILI 中的性别差异包括肝药物代谢或类固醇激素（如雄激素和雌激素）对肝脏信号通路的直接作用，但对于调节肝脏固有免疫反应中的性别差异知之甚少。在之前的一期 中，Bizzaro 及其同事分析了实验性急性肝损伤和再生中雄性和雌性小鼠之间的性别依赖性差异。作者观察到雄性动物的恢复过程存在时间延迟，与雌性动物相比，表达雄激素受体（AR）的单核细胞的募集增加。用药理学 AR 拮抗剂氟他胺治疗雄性小鼠可减少小鼠单核细胞的募集。同样，患有 DILI 的男性人类患者表现出更高的循环幼稚和潜在更具炎症性的单核细胞。总的来说，这些观察结果为急性肝损伤背景下的性别依赖性免疫机制提供了新的见解，提示 DILI 后存在性别差异的炎症和再生反应。
