Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI
Identifieur interne : 003D09 ( Ncbi/Checkpoint ); précédent : 003D08; suivant : 003D10Subtoxic 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
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DOI: 10.1155/2015/640631
PubMed: 26491234
PubMed Central: 4600928
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human <italic>In Vitro</italic> Liver Model: An Approach to Study DILI</title><author><name sortKey="Kegel, Victoria" sort="Kegel, Victoria" uniqKey="Kegel V" first="Victoria" last="Kegel">Victoria Kegel</name><affiliation wicri:level="3"><nlm:aff id="I1">Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Pfeiffer, Elisa" sort="Pfeiffer, Elisa" uniqKey="Pfeiffer E" first="Elisa" last="Pfeiffer">Elisa Pfeiffer</name><affiliation wicri:level="3"><nlm:aff id="I1">Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Burkhardt, Britta" sort="Burkhardt, Britta" uniqKey="Burkhardt B" first="Britta" last="Burkhardt">Britta Burkhardt</name><affiliation wicri:level="3"><nlm:aff id="I2">BG Trauma Center, Siegfried Weller Institute, Eberhard Karls University Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>BG Trauma Center, Siegfried Weller Institute, Eberhard Karls University Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Liu, Jia L" sort="Liu, Jia L" uniqKey="Liu J" first="Jia L." last="Liu">Jia L. Liu</name><affiliation wicri:level="3"><nlm:aff id="I1">Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Zeilinger, Katrin" sort="Zeilinger, Katrin" uniqKey="Zeilinger K" first="Katrin" last="Zeilinger">Katrin Zeilinger</name><affiliation wicri:level="3"><nlm:aff id="I3">Bioreactor Group, Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Bioreactor Group, Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Nussler, Andreas K" sort="Nussler, Andreas K" uniqKey="Nussler A" first="Andreas K." last="Nüssler">Andreas K. Nüssler</name><affiliation wicri:level="3"><nlm:aff id="I2">BG Trauma Center, Siegfried Weller Institute, Eberhard Karls University Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>BG Trauma Center, Siegfried Weller Institute, Eberhard Karls University Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Seehofer, Daniel" sort="Seehofer, Daniel" uniqKey="Seehofer D" first="Daniel" last="Seehofer">Daniel Seehofer</name><affiliation wicri:level="3"><nlm:aff id="I1">Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Damm, Georg" sort="Damm, Georg" uniqKey="Damm G" first="Georg" last="Damm">Georg Damm</name><affiliation wicri:level="3"><nlm:aff id="I1">Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26491234</idno><idno type="pmc">4600928</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600928</idno><idno type="RBID">PMC:4600928</idno><idno type="doi">10.1155/2015/640631</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000252</idno><idno type="wicri:Area/Pmc/Curation">000252</idno><idno type="wicri:Area/Pmc/Checkpoint">000310</idno><idno type="wicri:Area/Ncbi/Merge">003D09</idno><idno type="wicri:Area/Ncbi/Curation">003D09</idno><idno type="wicri:Area/Ncbi/Checkpoint">003D09</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human <italic>In Vitro</italic> Liver Model: An Approach to Study DILI</title><author><name sortKey="Kegel, Victoria" sort="Kegel, Victoria" uniqKey="Kegel V" first="Victoria" last="Kegel">Victoria Kegel</name><affiliation wicri:level="3"><nlm:aff id="I1">Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Pfeiffer, Elisa" sort="Pfeiffer, Elisa" uniqKey="Pfeiffer E" first="Elisa" last="Pfeiffer">Elisa Pfeiffer</name><affiliation wicri:level="3"><nlm:aff id="I1">Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Burkhardt, Britta" sort="Burkhardt, Britta" uniqKey="Burkhardt B" first="Britta" last="Burkhardt">Britta Burkhardt</name><affiliation wicri:level="3"><nlm:aff id="I2">BG Trauma Center, Siegfried Weller Institute, Eberhard Karls University Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>BG Trauma Center, Siegfried Weller Institute, Eberhard Karls University Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Liu, Jia L" sort="Liu, Jia L" uniqKey="Liu J" first="Jia L." last="Liu">Jia L. Liu</name><affiliation wicri:level="3"><nlm:aff id="I1">Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Zeilinger, Katrin" sort="Zeilinger, Katrin" uniqKey="Zeilinger K" first="Katrin" last="Zeilinger">Katrin Zeilinger</name><affiliation wicri:level="3"><nlm:aff id="I3">Bioreactor Group, Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Bioreactor Group, Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Nussler, Andreas K" sort="Nussler, Andreas K" uniqKey="Nussler A" first="Andreas K." last="Nüssler">Andreas K. Nüssler</name><affiliation wicri:level="3"><nlm:aff id="I2">BG Trauma Center, Siegfried Weller Institute, Eberhard Karls University Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>BG Trauma Center, Siegfried Weller Institute, Eberhard Karls University Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Seehofer, Daniel" sort="Seehofer, Daniel" uniqKey="Seehofer D" first="Daniel" last="Seehofer">Daniel Seehofer</name><affiliation wicri:level="3"><nlm:aff id="I1">Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Damm, Georg" sort="Damm, Georg" uniqKey="Damm G" first="Georg" last="Damm">Georg Damm</name><affiliation wicri:level="3"><nlm:aff id="I1">Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author></analytic><series><title level="j">Mediators of Inflammation</title><idno type="ISSN">0962-9351</idno><idno type="eISSN">1466-1861</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><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></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Schoonen, W G E J" uniqKey="Schoonen W">W. G. E. J. Schoonen</name></author><author><name sortKey="Westerink, W M A" uniqKey="Westerink W">W. M. A. Westerink</name></author><author><name sortKey="Horbach, G J" uniqKey="Horbach G">G. J. Horbach</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, M" uniqKey="Chen M">M. Chen</name></author><author><name sortKey="Vijay, V" uniqKey="Vijay V">V. 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Albrecht</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Koop, D R" uniqKey="Koop D">D. R. Koop</name></author><author><name sortKey="Chernosky, A" uniqKey="Chernosky A">A. Chernosky</name></author><author><name sortKey="Brass, E P" uniqKey="Brass E">E. P. Brass</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Parkinson, A" uniqKey="Parkinson A">A. Parkinson</name></author><author><name sortKey="Mudra, D R" uniqKey="Mudra D">D. R. Mudra</name></author><author><name sortKey="Johnson, C" uniqKey="Johnson C">C. Johnson</name></author><author><name sortKey="Dwyer, A" uniqKey="Dwyer A">A. Dwyer</name></author><author><name sortKey="Carroll, K M" uniqKey="Carroll K">K. M. Carroll</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yano, A" uniqKey="Yano A">A. Yano</name></author><author><name sortKey="Oda, S" uniqKey="Oda S">S. Oda</name></author><author><name sortKey="Fukami, T" uniqKey="Fukami T">T. Fukami</name></author><author><name sortKey="Nakajima, M" uniqKey="Nakajima M">M. Nakajima</name></author><author><name sortKey="Yokoi, T" uniqKey="Yokoi T">T. Yokoi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Roberts, R A" uniqKey="Roberts R">R. A. Roberts</name></author><author><name sortKey="Ganey, P E" uniqKey="Ganey P">P. E. Ganey</name></author><author><name sortKey="Ju, C" uniqKey="Ju C">C. Ju</name></author><author><name sortKey="Kamendulis, L M" uniqKey="Kamendulis L">L. M. Kamendulis</name></author><author><name sortKey="Rusyn, I" uniqKey="Rusyn I">I. Rusyn</name></author><author><name sortKey="Klaunig, J E" uniqKey="Klaunig J">J. E. Klaunig</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>Bade-Wurtemberg</li><li>Berlin</li><li>District de Tübingen</li></region><settlement><li>Berlin</li><li>Tübingen</li></settlement></list><tree><country name="Allemagne"><region name="Berlin"><name sortKey="Kegel, Victoria" sort="Kegel, Victoria" uniqKey="Kegel V" first="Victoria" last="Kegel">Victoria Kegel</name></region><name sortKey="Burkhardt, Britta" sort="Burkhardt, Britta" uniqKey="Burkhardt B" first="Britta" last="Burkhardt">Britta Burkhardt</name><name sortKey="Damm, Georg" sort="Damm, Georg" uniqKey="Damm G" first="Georg" last="Damm">Georg Damm</name><name sortKey="Liu, Jia L" sort="Liu, Jia L" uniqKey="Liu J" first="Jia L." last="Liu">Jia L. Liu</name><name sortKey="Nussler, Andreas K" sort="Nussler, Andreas K" uniqKey="Nussler A" first="Andreas K." last="Nüssler">Andreas K. Nüssler</name><name sortKey="Pfeiffer, Elisa" sort="Pfeiffer, Elisa" uniqKey="Pfeiffer E" first="Elisa" last="Pfeiffer">Elisa Pfeiffer</name><name sortKey="Seehofer, Daniel" sort="Seehofer, Daniel" uniqKey="Seehofer D" first="Daniel" last="Seehofer">Daniel Seehofer</name><name sortKey="Zeilinger, Katrin" sort="Zeilinger, Katrin" uniqKey="Zeilinger K" first="Katrin" last="Zeilinger">Katrin Zeilinger</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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