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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.940094/full |
| _version_ | 1818012970533257216 |
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| author | Siavash Raigani Siavash Raigani John Santiago Anders Ohman Megan Heaney Sofia Baptista Sofia Baptista Taylor M. Coe Reinier J. de Vries Ivy Rosales Angela Shih James F. Markmann James F. Markmann Philip Gruppuso Korkut Uygun Korkut Uygun Jennifer Sanders Heidi Yeh |
| author_facet | Siavash Raigani Siavash Raigani John Santiago Anders Ohman Megan Heaney Sofia Baptista Sofia Baptista Taylor M. Coe Reinier J. de Vries Ivy Rosales Angela Shih James F. Markmann James F. Markmann Philip Gruppuso Korkut Uygun Korkut Uygun Jennifer Sanders Heidi Yeh |
| author_sort | Siavash Raigani |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-14T06:27:36Z |
| format | Article |
| id | doaj.art-064a03be192941aab614bfdaa91a5851 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-14T06:27:36Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-064a03be192941aab614bfdaa91a58512022-12-22T02:07:45ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-07-011310.3389/fimmu.2022.940094940094Pan-caspase inhibition during normothermic machine perfusion of discarded livers mitigates ex situ innate immune responsesSiavash Raigani0Siavash Raigani1John Santiago2Anders Ohman3Megan Heaney4Sofia Baptista5Sofia Baptista6Taylor M. Coe7Reinier J. de Vries8Ivy Rosales9Angela Shih10James F. Markmann11James F. Markmann12Philip Gruppuso13Korkut Uygun14Korkut Uygun15Jennifer Sanders16Heidi Yeh17Division of Transplant Surgery, Massachusetts General Hospital, Boston, MA, United StatesCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesDepartment of Pediatrics, Rhode Island Hospital and Brown University, Providence, RI, United StatesDepartment of Pediatrics, Rhode Island Hospital and Brown University, Providence, RI, United StatesDepartment of Pediatrics, Rhode Island Hospital and Brown University, Providence, RI, United StatesDivision of Transplant Surgery, Massachusetts General Hospital, Boston, MA, United StatesCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesDivision of Transplant Surgery, Massachusetts General Hospital, Boston, MA, United StatesCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesDepartment of Pathology, Massachusetts General Hospital, Boston, MA, United StatesDepartment of Pathology, Massachusetts General Hospital, Boston, MA, United StatesDivision of Transplant Surgery, Massachusetts General Hospital, Boston, MA, United StatesCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesDivision of Transplant Surgery, Massachusetts General Hospital, Boston, MA, United StatesCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesDepartment of Pediatrics, Rhode Island Hospital and Brown University, Providence, RI, United StatesDivision of Transplant Surgery, Massachusetts General Hospital, Boston, MA, United StatesAccess 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.https://www.frontiersin.org/articles/10.3389/fimmu.2022.940094/fullmachine perfusionliver transplantapoptosiscaspasenormothermicischemia reperfusion injury |
| spellingShingle | Siavash Raigani Siavash Raigani John Santiago Anders Ohman Megan Heaney Sofia Baptista Sofia Baptista Taylor M. Coe Reinier J. de Vries Ivy Rosales Angela Shih James F. Markmann James F. Markmann Philip Gruppuso Korkut Uygun Korkut Uygun Jennifer Sanders Heidi Yeh Pan-caspase inhibition during normothermic machine perfusion of discarded livers mitigates ex situ innate immune responses Frontiers in Immunology machine perfusion liver transplant apoptosis caspase normothermic ischemia reperfusion injury |
| 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 | machine perfusion liver transplant apoptosis caspase normothermic ischemia reperfusion injury |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.940094/full |
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