Division of Transplant Surgery, Massachusetts General Hospital, Boston, MA, United States.
Center for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
Front Immunol. 2022 Jul 26;13:940094. doi: 10.3389/fimmu.2022.940094. eCollection 2022.
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.
肝移植的供体器官严重短缺，限制了其应用。最近，机器灌注技术的出现使外科医生可以在移植前监测和评估离体肝脏的功能。然而，许多捐献的器官质量不足以用于移植，尽管在常温机器灌注期间可以通过辅助治疗来恢复器官功能。在这项临床前研究中，我们将细胞凋亡途径作为一种提高肝细胞功能的潜在方法。在常温灌注期间，不可逆的多半胱氨酸天冬氨酸蛋白酶抑制剂 emricasan 处理废弃的人类肝脏，在转录和蛋白水平上显著减轻固有免疫和促炎反应。与对照肝脏相比，这表现为促炎细胞因子白细胞介素 6、白细胞介素 8 和干扰素-γ的循环水平显著降低。与 emricasan 处理的肝脏相比，未处理的肝脏表现出转录变化，显著富集了涉及固有免疫、白细胞迁移和细胞因子介导的信号转导的途径。在机器灌注期间调节不受控制的细胞凋亡可能是一种可行的免疫调节治疗干预措施。
