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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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.
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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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