Trovafloxacin-induced liver injury: lack in regulation of inflammation by inhibition of nucleotide release and neutrophil movement
Giustarini, Giulio; Vrisekoop, Nienke; Kruijssen, Laura; Wagenaar, Laura; van Staveren, Selma; van Roest, Manon; Bleumink, Rob; Bol-Schoenmakers, Marianne; Weaver, Richard; Koenderman, Leo; Smit, Joost; Pieters, Raymond
(2019) Toxicological sciences : an official journal of the Society of Toxicology, volume 167, issue 2, pp. 385 - 396
(Article)
Abstract
The fluoroquinolone trovafloxacin (TVX) is associated with a high risk of drug-induced liver injury (DILI). Although part of the liver damage by TVX+TNF relies on neutrophils, we have recently demonstrated that liver recruitment of monocytes and neutrophils is delayed by TVX.Here we show that the delayed leukocyte recruitment is caused
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by a combination of effects which are linked to the capacity of TVX to block the hemichannel pannexin 1. TVX inhibited find-me signal release in apoptotic HepG2 hepatocytes, decelerated freshly isolated human neutrophils toward IL-8 and f-MLF, and decreased the liver expression of ICAM-1. In blood of TVX+TNF-treated mice we observed an accumulation of activated neutrophils despite an increased MIP-2 release by the liver.Depletion of monocytes and neutrophils caused increased serum concentrations of TNF, IL-6 and MIP-2 in TVX-treated mice as well as in mice treated with the fluoroquinolone levofloxacin, known to have a lower DILI-inducing profile. This supports the idea that early leukocyte recruitment regulates inflammation.In conclusion, disrupted regulation by leukocytes appears to constitute a fundamental step in the onset of TVX-induced liver injury, acting in concert with the capability of TVX to induce hepatocyte cell death.Interference of leukocyte-mediated regulation of inflammation represents a novel mechanism to explain the onset of DILI.
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Keywords: Journal Article, monocytes, Dili, trovafloxacin, nucleotide release, regulation of inflammation, neutrophils, Intercellular Adhesion Molecule-1/metabolism, Humans, Mice, Inbred C57BL, Male, Nucleotides/metabolism, Inflammation, Hep G2 Cells, Animals, Nerve Tissue Proteins/metabolism, Neutrophils/drug effects, Neutrophil Infiltration/drug effects, Fluoroquinolones/toxicity, Chemical and Drug Induced Liver Injury/immunology, Connexins/metabolism, Anti-Infective Agents/toxicity, Naphthyridines/toxicity, Tumor Necrosis Factor-alpha/toxicity, DILI, Toxicology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 1096-0929
(Peer reviewed)