Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Human and Environmental Toxicology, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea.
Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea.
Toxicol In Vitro. 2022 Aug;82:105374. doi: 10.1016/j.tiv.2022.105374. Epub 2022 May 9.
Drug-induced liver injury (DILI) is an adverse hepatic reaction and a serious concern for public healthcare systems and pharmaceutical companies. DILI is frequently caused by a combination of direct toxic stresses and subsequent immune damage to hepatocytes. However, little is known about the mechanism by which drugs facilitate the activation of the innate immune system. Here, we aimed to decipher the inflammatory events in trovafloxacin (TVX)-induced reactions using liver macrophages. We showed that proinflammatory M1-like macrophages mainly contributed to hepatotoxicity mediated by TVX, a DILI drug. Additionally, transcriptome results showed that the interferon type I pathway, cytokines, and apoptosis pathway were involved in the initiation of synergistic effects resulting in TVX-induced liver injury. We hypothesized that DILI drugs could drive liver injury by altering the activation and phenotype of hepatic macrophages. Furthermore, drug treatment-induced transcriptional changes such as Traf1 and 2, Socs3, and Hbegf in macrophage polarization could be used to assess drug-specific immune-mediated reactions. Therefore, we proposed that transcriptional change in the genes related to macrophage polarization index could be an indicator to reflect the severity of DILI in a preclinical setting during drug development.
药物性肝损伤（DILI）是一种不良的肝脏反应，对公共医疗保健系统和制药公司构成严重关切。DILI 通常是由直接毒性应激和随后对肝细胞的免疫损伤共同引起的。然而，关于药物如何促进固有免疫系统激活的机制知之甚少。在这里，我们旨在使用肝巨噬细胞来解析曲伐沙星（TVX）诱导反应中的炎症事件。我们表明，促炎 M1 样巨噬细胞主要导致 TVX 介导的肝毒性，TVX 是一种 DILI 药物。此外，转录组结果表明，I 型干扰素途径、细胞因子和细胞凋亡途径参与了导致 TVX 诱导的肝损伤的协同作用的启动。我们假设 DILI 药物可以通过改变肝巨噬细胞的激活和表型来导致肝损伤。此外，药物治疗诱导的转录变化，如巨噬细胞极化中的 Traf1 和 2、SocS3 和 Hbegf，可以用于评估药物特异性免疫介导的反应。因此，我们提出与巨噬细胞极化指数相关的基因的转录变化可以作为在药物开发的临床前阶段反映 DILI 严重程度的指标。
