Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI
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 hu...
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| Format: | Article |
| Language: | English |
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Wiley
2015-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2015/640631 |
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| author | Victoria Kegel Elisa Pfeiffer Britta Burkhardt Jia L. Liu Katrin Zeilinger Andreas K. Nüssler Daniel Seehofer Georg Damm |
| author_facet | Victoria Kegel Elisa Pfeiffer Britta Burkhardt Jia L. Liu Katrin Zeilinger Andreas K. Nüssler Daniel Seehofer Georg Damm |
| author_sort | Victoria Kegel |
| collection | DOAJ |
| description | 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 in vitro 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±0.9×106 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 in vitro liver model. KC were able to detect hepatocyte stress/damage and to transmit a donor- and compound-dependent immune response via cytokine production. |
| format | Article |
| id | doaj-art-fd2a1c39d0d74523b35e1a5d8ecee5bc |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-fd2a1c39d0d74523b35e1a5d8ecee5bc2025-02-03T01:20:22ZengWileyMediators of Inflammation0962-93511466-18612015-01-01201510.1155/2015/640631640631Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILIVictoria Kegel0Elisa Pfeiffer1Britta Burkhardt2Jia L. Liu3Katrin Zeilinger4Andreas K. Nüssler5Daniel Seehofer6Georg Damm7Department of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyDepartment of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyBG Trauma Center, Siegfried Weller Institute, Eberhard Karls University Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen, GermanyDepartment of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyBioreactor Group, Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyBG Trauma Center, Siegfried Weller Institute, Eberhard Karls University Tübingen, Schnarrenbergstrasse 95, 72076 Tübingen, GermanyDepartment of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyDepartment of General, Visceral and Transplantation Surgery, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyDrug 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 in vitro 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±0.9×106 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 in vitro liver model. KC were able to detect hepatocyte stress/damage and to transmit a donor- and compound-dependent immune response via cytokine production.http://dx.doi.org/10.1155/2015/640631 |
| spellingShingle | Victoria Kegel Elisa Pfeiffer Britta Burkhardt Jia L. Liu Katrin Zeilinger Andreas K. Nüssler Daniel Seehofer Georg Damm Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI Mediators of Inflammation |
| title | Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI |
| title_full | Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI |
| title_fullStr | Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI |
| title_full_unstemmed | Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI |
| title_short | Subtoxic Concentrations of Hepatotoxic Drugs Lead to Kupffer Cell Activation in a Human In Vitro Liver Model: An Approach to Study DILI |
| title_sort | subtoxic concentrations of hepatotoxic drugs lead to kupffer cell activation in a human in vitro liver model an approach to study dili |
| url | http://dx.doi.org/10.1155/2015/640631 |
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