Division of Liver and Pancreas Transplantation, Department of Surgery, The Dumont-UCLA Transplant Center, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
Am J Transplant. 2018 Jul;18(7):1755-1763. doi: 10.1111/ajt.14706. Epub 2018 Mar 23.
Liver ischemia-reperfusion injury (IRI) represents a risk factor for early graft dysfunction and an obstacle to expanding donor pool in orthotopic liver transplantation (OLT). We have reported on the crucial role of macrophage Notch1 signaling in mouse warm hepatic IRI model. However, its clinical relevance or therapeutic potential remain unknown. Here, we used Serelaxin (SER), to verify Notch1 induction and putative hepatoprotective function in ischemia-reperfusion-stressed OLT. C57BL/6 mouse livers subjected to extended (18-hour) cold storage were transplanted to syngeneic recipients. SER treatment at reperfusion ameliorated IRI, improved post-OLT survival, decreased neutrophil/macrophage infiltration, and suppressed proinflammatory cytokine programs, while simultaneously increasing Notch intracellular domain (NICD) and hairy and enhancer of split 1 (Hes1) target genes. In bone marrow-derived macrophage cultures, SER suppressed proinflammatory while enhancing antiinflammatory gene expression concomitantly with increased NICD and Hes1. Hepatic biopsies from 21 adult primary liver transplant patients (2 hours postreperfusion) were divided into low-NICD (n = 11) and high-NICD (n = 10) expression groups (western blots). Consistent with our murine findings, human livers characterized by high NICD were relatively IRI resistant, as shown by serum alanine aminotransferase (ALT) levels at day 1 post-OLT. Our study documents the efficacy of SER-Notch1 signaling in mouse OLT and highlights the protective function of Notch1 in liver transplant patients.
肝缺血再灌注损伤（IRI）是导致肝移植早期移植物功能障碍的危险因素，也是扩大供体池的障碍。我们已经报道了巨噬细胞 Notch1 信号在小鼠热肝 IRI 模型中的关键作用。然而，其临床相关性或治疗潜力尚不清楚。在这里，我们使用 Serelaxin（SER），在缺血再灌注应激的肝移植中验证 Notch1 的诱导和潜在的肝保护作用。将 C57BL/6 小鼠肝脏进行 18 小时的冷保存后移植到同基因受体中。在再灌注时给予 SER 治疗可改善 IRI，提高肝移植后的存活率，减少中性粒细胞/巨噬细胞浸润，并抑制促炎细胞因子程序，同时增加 Notch 细胞内结构域（NICD）和毛状和增强子分裂 1（Hes1）靶基因。在骨髓来源的巨噬细胞培养物中，SER 抑制促炎基因的表达，同时增强抗炎基因的表达，同时增加 NICD 和 Hes1。21 例成人原发性肝移植患者（再灌注后 2 小时）的肝活检标本分为低 NICD（n=11）和高 NICD（n=10）表达组（western blot）。与我们的小鼠研究结果一致，具有高 NICD 的人类肝脏相对IRI 抵抗，表现为肝移植后第 1 天血清丙氨酸氨基转移酶（ALT）水平。我们的研究证明了 SER-Notch1 信号在小鼠肝移植中的疗效，并强调了 Notch1 在肝移植患者中的保护作用。
