Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI
Identifieur interne : 000527 ( Main/Exploration ); précédent : 000526; suivant : 000528Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI
Auteurs : Victoria Kegel [Allemagne] ; Elisa Pfeiffer [Allemagne] ; Britta Burkhardt [Allemagne] ; Jia L. Liu [Allemagne] ; Katrin Zeilinger [Allemagne] ; Andreas K. Nüssler [Allemagne] ; Daniel Seehofer [Allemagne] ; Georg Damm [Allemagne]Source :
- Mediators of Inflammation [ 0962-9351 ] ; 2015.
Abstract
Drug induced liver injury (DILI) is an idiosyncratic adverse drug reaction leading to severe liver damage. Kupffer cells (KC) sense hepatic tissue stress/damage and therefore could be a tool for the estimation of consequent effects associated with DILI. Aim of the present study was to establish a human
Url:
DOI: 10.1155/2015/640631
PubMed: 26491234
PubMed Central: 4600928
Affiliations:
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<author><name sortKey="Damm, Georg" sort="Damm, Georg" uniqKey="Damm G" first="Georg" last="Damm">Georg Damm</name>
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<series><title level="j">Mediators of Inflammation</title>
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<front><div type="abstract" xml:lang="en"><p>Drug induced liver injury (DILI) is an idiosyncratic adverse drug reaction leading to severe liver damage. Kupffer cells (KC) sense hepatic tissue stress/damage and therefore could be a tool for the estimation of consequent effects associated with DILI. Aim of the present study was to establish a human <italic>in vitro</italic>
liver model for the investigation of immune-mediated signaling in the pathogenesis of DILI. Hepatocytes and KC were isolated from human liver specimens. The isolated KC yield was 1.2 ± 0.9 × 10<sup>6</sup>
cells/g liver tissue with a purity of >80%. KC activation was investigated by the measurement of reactive oxygen intermediates (ROI, DCF assay) and cell activity (XTT assay). The initial KC activation levels showed broad donor variability. Additional activation of KC using supernatants of hepatocytes treated with hepatotoxic drugs increased KC activity and led to donor-dependent changes in the formation of ROI compared to KC incubated with supernatants from untreated hepatocytes. Additionally, a compound- and donor-dependent increase in proinflammatory cytokines or in anti-inflammatory cytokines was detected. In conclusion, KC related immune signaling in hepatotoxicity was successfully determined in a newly established <italic>in vitro</italic>
liver model. KC were able to detect hepatocyte stress/damage and to transmit a donor- and compound-dependent immune response via cytokine production.</p>
</div>
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<affiliations><list><country><li>Allemagne</li>
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<region><li>Bade-Wurtemberg</li>
<li>Berlin</li>
<li>District de Tübingen</li>
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<name sortKey="Liu, Jia L" sort="Liu, Jia L" uniqKey="Liu J" first="Jia L." last="Liu">Jia L. Liu</name>
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