4.5 Article

Trovafloxacin drives inflammation-associated drug-induced adverse hepatic reaction by changing macrophage polarization

期刊

TOXICOLOGY IN VITRO
卷 82, 期 -, 页码 -

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2022.105374

关键词

Drug-induced liver injury; Kupffer cell; Inflammation; Macrophage polarization index; Trovafloxacin

资金

  1. Korea Institute of Toxicology grant [1711159817]
  2. National Research Foundation of Korea (NRF) [NRF-2020R1A2C4002109]

向作者/读者索取更多资源

Drug-induced liver injury (DILI) is a serious concern for public healthcare systems and pharmaceutical companies. This study investigates the mechanism by which DILI drugs alter the activation and phenotype of hepatic macrophages. The findings suggest that proinflammatory M1-like macrophages contribute to hepatotoxicity mediated by DILI drugs, and the interferon type I pathway, cytokines, and apoptosis pathway are involved in the initiation of liver injury. Transcriptional changes in genes related to macrophage polarization could be used as indicators to reflect the severity of DILI during drug development.
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 treatmentinduced 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.

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