Trovafloxacin drives inflammation-associated drug-induced adverse hepatic reaction by changing macrophage polarization.
In: Toxicology in Vitro, Jg. 82 (2022-08-01), S. N.PAG
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Zugriff:
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. • Drug-induced liver injury (DILI) is an adverse drug reaction and its prediction remains extremely challenging. Further, drug-induced innate immune response such as inflammation can amplify liver tissue damage. • In this study, we found that the proinflammatory M1 macrophage is mainly activated, promoting trovafloxacin (TVX)-induced liver injury by the release of high levels of proinflammatory cytokines (TNF-α). • Further, the transcriptome in liver macrophages exposed to TVX suggests candidate biomarker genes to improve the early detection of immunological DILI in the absence of diagnostic DILI biomarkers. [ABSTRACT FROM AUTHOR]
Titel: |
Trovafloxacin drives inflammation-associated drug-induced adverse hepatic reaction by changing macrophage polarization.
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Autor/in / Beteiligte Person: | Yang, Heeyoung ; Park, Tamina ; Park, Daeui ; Kang, Myung-Gyun |
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Zeitschrift: | Toxicology in Vitro, Jg. 82 (2022-08-01), S. N.PAG |
Veröffentlichung: | 2022 |
Medientyp: | academicJournal |
ISSN: | 0887-2333 (print) |
DOI: | 10.1016/j.tiv.2022.105374 |
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