Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA; Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Surgery, Nishi-Kobe Medical Center, 5-7-1 Koji-dai, Nishi-ku, Kobe, Hyogo, 651-2273, Japan.
Free Radic Biol Med. 2020 Sep;157:75-82. doi: 10.1016/j.freeradbiomed.2020.02.012. Epub 2020 Feb 19.
Hepatic ischemia-reperfusion injury (IRI), a major risk factor for early allograft dysfunction (EAD) and acute or chronic graft rejection, contributes to donor organ shortage for life-saving orthotopic liver transplantation (OLT). The graft injury caused by local ischemia (warm and/or cold) leads to parenchymal cell death and release of danger-associated molecular patterns (DAMPs), followed by reperfusion-triggered production of reactive oxygen species (ROS), activation of inflammatory cells, hepatocellular damage and ultimate organ failure. Heme oxygenase 1 (HO-1), a heat shock protein-32 induced under IR-stress, is an essential component of the cytoprotective mechanism in stressed livers. HO-1 regulates anti-inflammatory responses and may be crucial in the pathogenesis of chronic diseases, such as arteriosclerosis, hypertension, diabetes and steatosis. An emerging area of study is macrophage-derived HO-1 and its pivotal intrahepatic homeostatic function played in IRI-OLT. Indeed, ectopic hepatic HO-1 overexpression activates intracellular SIRT1/autophagy axis to serve as a key cellular self-defense mechanism in both mouse and human OLT recipients. Recent translational studies in rodents and human liver transplant patients provide novel insights into HO-1 mediated cytoprotection against sterile hepatic inflammation. In this review, we summarize the current bench-to-bedside knowledge on HO-1 molecular signaling and discuss their future therapeutic potential to mitigate IRI in OLT.
肝缺血再灌注损伤（IRI）是导致早期移植物功能障碍（EAD）和急性或慢性移植物排斥的主要危险因素，导致用于挽救生命的原位肝移植（OLT）的供体器官短缺。局部缺血（热和/或冷）引起的供体损伤导致实质细胞死亡和危险相关分子模式（DAMPs）的释放，随后再灌注触发活性氧（ROS）的产生、炎症细胞的激活、肝细胞损伤和最终的器官衰竭。HO-1 是热休克蛋白-32 在 IR 应激下诱导的一种血红素加氧酶，是应激状态下肝脏保护机制的重要组成部分。HO-1 调节抗炎反应，在动脉粥样硬化、高血压、糖尿病和脂肪变性等慢性疾病的发病机制中可能至关重要。一个新兴的研究领域是巨噬细胞衍生的 HO-1 及其在 IRI-OLT 中的关键肝内稳态功能。事实上，肝脏 HO-1 的异位过表达激活细胞内 SIRT1/自噬轴，作为小鼠和人类 OLT 受者中关键的细胞自身防御机制。最近在啮齿动物和人类肝移植患者中的转化研究为 HO-1 介导的对无菌性肝炎症的细胞保护作用提供了新的见解。在这篇综述中，我们总结了 HO-1 分子信号的当前基础到临床知识，并讨论了它们在减轻 OLT 中 IRI 方面的未来治疗潜力。
