Biliverdin therapy protects rat livers from ischemia and reperfusion injury
Biliverdin therapy protects rat livers from ischemia and reperfusion injury
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DOI：
10.1002/hep.20480
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发表时间：
2004-12-01
期刊：
影响因子：
13.5
通讯作者：
Bach, FH
中科院分区：
文献类型：
--
作者：
Fondevila, C;Shen, XD;Bach, FH
血红素加氧酶（HO-1）在氧化应激过程中提供细胞防御机制，并催化血红素代谢中的限速步骤，产生胆绿素（BV）。BV的作用及其在预防缺血/再灌注损伤（IRI）中的潜在用途尚未研究。本研究旨在探讨BV在长时间冷缺血后离体灌注和原位肝移植（奥尔特）大鼠肝脏模型中肝脏IRI期间的细胞保护功能。在离体肝脏IRI模型中，连续BV改善门静脉血流量，增加胆汁产生，并减少肝细胞损伤。这些发现与IRI的组织学特征的改善相关，正如Suzuki标准所评估的那样。在冷缺血和同基因奥尔特后，BV治疗将动物存活率从未治疗对照组的50%延长至90%至100%。这种作用与改善肝功能和保留肝脏结构相关。此外，奥尔特后BV佐剂降低了细胞粘附分子（P-选择素和细胞内粘附分子1）的内皮表达，并降低了中性粒细胞和炎性巨噬细胞的浸润程度。BV还抑制OLT中诱导型一氧化氮合酶和促炎细胞因子（白介素1 β、肿瘤坏死因子α和白介素6）的表达。最后，BV治疗促进了独立于HO-1表达的抗凋亡分子表达的增加，这与BV是HO-1预防细胞死亡的重要介质一致。总之，本研究记录并分析了BV在已建立的肝IRI大鼠模型中的强效细胞保护作用。我们的研究结果提供了一种新的治疗方法，使用BV，以最大限度地提高功能，从而供体器官的可用性的基本原理。
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.