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Pan-caspase inhibition during normothermic machine perfusion of discarded livers mitigates ex situ innate immune responses
Access to liver transplantation is limited by a significant organ shortage. The recent introduction of machine perfusion technology allows surgeons to monitor and assess ex situ liver function prior to transplantation. However, many donated organs are of inadequate quality for transplant, though opp...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9360556/ https://www.ncbi.nlm.nih.gov/pubmed/35958587 http://dx.doi.org/10.3389/fimmu.2022.940094 |
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author | Raigani, Siavash Santiago, John Ohman, Anders Heaney, Megan Baptista, Sofia Coe, Taylor M. de Vries, Reinier J. Rosales, Ivy Shih, Angela Markmann, James F. Gruppuso, Philip Uygun, Korkut Sanders, Jennifer Yeh, Heidi |
author_facet | Raigani, Siavash Santiago, John Ohman, Anders Heaney, Megan Baptista, Sofia Coe, Taylor M. de Vries, Reinier J. Rosales, Ivy Shih, Angela Markmann, James F. Gruppuso, Philip Uygun, Korkut Sanders, Jennifer Yeh, Heidi |
author_sort | Raigani, Siavash |
collection | PubMed |
description | Access to liver transplantation is limited by a significant organ shortage. The recent introduction of machine perfusion technology allows surgeons to monitor and assess ex situ liver function prior to transplantation. However, many donated organs are of inadequate quality for transplant, though opportunities exist to rehabilitate organ function with adjunct therapeutics during normothermic machine perfusion. In this preclinical study, we targeted the apoptosis pathway as a potential method of improving hepatocellular function. Treatment of discarded human livers during normothermic perfusion with an irreversible pan-caspase inhibitor, emricasan, resulted in significant mitigation of innate immune and pro-inflammatory responses at both the transcriptional and protein level. This was evidenced by significantly decreased circulating levels of the pro-inflammatory cytokines, interleukin-6, interleukin-8, and interferon-gamma, compared to control livers. Compared to emricasan-treated livers, untreated livers demonstrated transcriptional changes notable for enrichment in pathways involved in innate immunity, leukocyte migration, and cytokine-mediated signaling. Targeting of unregulated apoptosis may represent a viable therapeutic intervention for immunomodulation during machine perfusion. |
format | Online Article Text |
id | pubmed-9360556 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93605562022-08-10 Pan-caspase inhibition during normothermic machine perfusion of discarded livers mitigates ex situ innate immune responses Raigani, Siavash Santiago, John Ohman, Anders Heaney, Megan Baptista, Sofia Coe, Taylor M. de Vries, Reinier J. Rosales, Ivy Shih, Angela Markmann, James F. Gruppuso, Philip Uygun, Korkut Sanders, Jennifer Yeh, Heidi Front Immunol Immunology Access to liver transplantation is limited by a significant organ shortage. The recent introduction of machine perfusion technology allows surgeons to monitor and assess ex situ liver function prior to transplantation. However, many donated organs are of inadequate quality for transplant, though opportunities exist to rehabilitate organ function with adjunct therapeutics during normothermic machine perfusion. In this preclinical study, we targeted the apoptosis pathway as a potential method of improving hepatocellular function. Treatment of discarded human livers during normothermic perfusion with an irreversible pan-caspase inhibitor, emricasan, resulted in significant mitigation of innate immune and pro-inflammatory responses at both the transcriptional and protein level. This was evidenced by significantly decreased circulating levels of the pro-inflammatory cytokines, interleukin-6, interleukin-8, and interferon-gamma, compared to control livers. Compared to emricasan-treated livers, untreated livers demonstrated transcriptional changes notable for enrichment in pathways involved in innate immunity, leukocyte migration, and cytokine-mediated signaling. Targeting of unregulated apoptosis may represent a viable therapeutic intervention for immunomodulation during machine perfusion. Frontiers Media S.A. 2022-07-26 /pmc/articles/PMC9360556/ /pubmed/35958587 http://dx.doi.org/10.3389/fimmu.2022.940094 Text en Copyright © 2022 Raigani, Santiago, Ohman, Heaney, Baptista, Coe, de Vries, Rosales, Shih, Markmann, Gruppuso, Uygun, Sanders and Yeh https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Raigani, Siavash Santiago, John Ohman, Anders Heaney, Megan Baptista, Sofia Coe, Taylor M. de Vries, Reinier J. Rosales, Ivy Shih, Angela Markmann, James F. Gruppuso, Philip Uygun, Korkut Sanders, Jennifer Yeh, Heidi Pan-caspase inhibition during normothermic machine perfusion of discarded livers mitigates ex situ innate immune responses |
title | Pan-caspase inhibition during normothermic machine perfusion of discarded livers mitigates ex situ innate immune responses |
title_full | Pan-caspase inhibition during normothermic machine perfusion of discarded livers mitigates ex situ innate immune responses |
title_fullStr | Pan-caspase inhibition during normothermic machine perfusion of discarded livers mitigates ex situ innate immune responses |
title_full_unstemmed | Pan-caspase inhibition during normothermic machine perfusion of discarded livers mitigates ex situ innate immune responses |
title_short | Pan-caspase inhibition during normothermic machine perfusion of discarded livers mitigates ex situ innate immune responses |
title_sort | pan-caspase inhibition during normothermic machine perfusion of discarded livers mitigates ex situ innate immune responses |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9360556/ https://www.ncbi.nlm.nih.gov/pubmed/35958587 http://dx.doi.org/10.3389/fimmu.2022.940094 |
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