Tissue influx of neutrophils and monocytes is delayed during development of trovafloxacin-induced tumor necrosis factor-dependent liver injury in mice

Idiosyncratic drug-induced liver injury (iDILI) has a poorly understood pathogenesis. However, iDILI is often associated with inflammatory stress signals in human patients as well as animal models. Tumor necrosis factor (TNF) and neutrophils play a key role in onset of trovafloxacin (TVX)-induced iDILI, but the exact role of neutrophils and other leukocytes remains to be defined. We therefore set out to study the kinetics of immunological changes during the development of TVX-induced iDILI in the established murine model of acute liver injury induced by administration of TVX and TNF. Initially, TNF stimulated the appearance of leukocytes, in particular neutrophils, into the liver of TVX-treated mice, but even more so in control mice treated with the non-DILI inducing analogue levofloxacin (LVX) or saline as vehicle (Veh). This difference was apparent at 2hours after TNF administration, but at 4hours, the relative neutrophil amounts were reduced again in Veh- and LVX-treated mice whereas the amounts in TVX-treated mice remained at the same increased level as at 2hours. The influx of monocytes/macrophages, which was unaffected in Veh- and LVX-treated mice was markedly reduced or even absent in TVX-treated mice. Unlike controls, mice receiving TVX + TNF display severe hepatotoxicity with clear pathology and apoptosis, coagulated hepatic vessels and increased alanine aminotransferase levels and interleukin 6/10 ratios. Findings indicate that TVX delays the acute influx of neutrophils and monocytes/macrophages. Considering their known anti-inflammatory functions, the disruption of influx of these innate immune cells may hamper the resolution of initial cytotoxic effects of TVX and thus contribute to liver injury development. The role of innate immune system in the onset of idiosyncratic drug-induced liver injury is still matter of debate. Recent findings revealed how inflammation represents a key player in idiosyncratic drug-induced liver injury. We evaluated the effects of trovafloxacin on the inflammation induced by tumor necrosis factor in mouse and found that trovafloxacin delays neutrophil and monocyte influx in mice livers. Considering the known neutrophil and monocyte anti-inflammatory functions, the observed effect may hinder the regulation of inflammation contributing to the development of liver injury.