Fondevila Constantino, Shen Xiu-Da, Tsuchiyashi Seiichiro, Yamashita Kenichiro, Csizmadia Eva, Lassman Charles, Busuttil Ronald W, Kupiec-Weglinski Jerzy W, Bach Fritz H
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-7054, USA.
Hepatology. 2004 Dec;40(6):1333-41. doi: 10.1002/hep.20480.
Heme oxygenase (HO-1) provides a cellular defense mechanism during oxidative stress and catalyzes the rate-limiting step in heme metabolism that produces biliverdin (BV). The role of BV and its potential use in preventing ischemia/reperfusion injury (IRI) had never been studied. This study was designed to explore putative cytoprotective functions of BV during hepatic IRI in rat liver models of ex vivo perfusion and orthotopic liver transplantation (OLT) after prolonged periods of cold ischemia. In an ex vivo hepatic IRI model, adjunctive BV improved portal venous blood flow, increased bile production, and decreased hepatocellular damage. These findings were correlated with amelioration of histological features of IRI, as assessed by Suzuki's criteria. Following cold ischemia and syngeneic OLT, BV therapy extended animal survival from 50% in untreated controls to 90% to 100%. This effect correlated with improved liver function and preserved hepatic architecture. Additionally, BV adjuvant after OLT decreased endothelial expression of cellular adhesion molecules (P-selectin and intracellular adhesion molecule 1), and decreased the extent of infiltration by neutrophils and inflammatory macrophages. BV also inhibited expression of inducible nitric oxide synthase and proinflammatory cytokines (interleukin 1beta, tumor necrosis factor alpha, and interleukin 6) in OLTs. Finally, BV therapy promoted an increased expression of antiapoptotic molecules independently of HO-1 expression, consistent with BV being an important mediator through which HO-1 prevents cell death. In conclusion, this study documents and dissects potent cytoprotective effects of BV in well-established rat models of hepatic IRI. Our results provide the rationale for a novel therapeutic approach using BV to maximize the function and thus the availability of donor organs.
血红素加氧酶（HO-1）在氧化应激期间提供细胞防御机制，并催化血红素代谢中产生胆绿素（BV）的限速步骤。BV的作用及其在预防缺血/再灌注损伤（IRI）中的潜在用途从未被研究过。本研究旨在探讨在长时间冷缺血后的离体灌注和原位肝移植（OLT）大鼠肝模型中BV在肝IRI期间的假定细胞保护功能。在离体肝IRI模型中，辅助使用BV可改善门静脉血流、增加胆汁生成并减少肝细胞损伤。根据铃木标准评估，这些发现与IRI组织学特征的改善相关。在冷缺血和同基因OLT后，BV治疗将动物存活率从未经治疗对照组的50%提高到90%至100%。这一效果与肝功能改善和肝脏结构保存相关。此外，OLT后使用BV辅助剂可降低细胞黏附分子（P-选择素和细胞间黏附分子1）的内皮表达，并减少中性粒细胞和炎性巨噬细胞浸润的程度。BV还抑制OLT中诱导型一氧化氮合酶和促炎细胞因子（白细胞介素1β、肿瘤坏死因子α和白细胞介素6）的表达。最后，BV治疗促进抗凋亡分子表达增加，且与HO-1表达无关，这与BV是HO-1预防细胞死亡的重要介质一致。总之，本研究记录并剖析了BV在成熟大鼠肝IRI模型中的强大细胞保护作用。我们的结果为使用BV的新型治疗方法提供了理论依据，以最大限度地发挥供体器官的功能并提高其可用性。
