Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury
Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury
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DOI：
10.1172/jci7903
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发表时间：
1999-12-01
影响因子：
15.9
通讯作者：
Kupiec-Weglinski, JW
中科院分区：
文献类型：
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作者：
Amersi, F;Buelow, R;Kupiec-Weglinski, JW
我们观察了血红素加氧酶-L(HO-1)在脂肪变性大鼠肝脏冷缺血/再灌注(I/R)损伤模型中的上调作用。在缺血/隔离灌流模型中，HO-1诱导剂钴原卟啉(CoPP)或腺病毒HO-1(Ad-HO-1)治疗遗传性肥胖的Zucker大鼠显著改善门静脉血流量，增加胆汁生成，减轻肝细胞损伤。与未治疗的大鼠或用HO-1抑制剂锌原卟啉(ZnPP)预处理的大鼠不同，Western blotting上调HO-1与改善I/R损伤的组织学特征有关。辅助性注射ZnPP可阻断Ad-HO-1基因转移的有利作用，证明HO-1直接参与了对I/R损伤的保护作用。在冷缺血/同种异体移植后，HO-1的过表达延长了动物的存活率，从未经处理的对照组的40%延长到CoPP或Ad-HO-1治疗后的约80%。这种效应与保存肝脏结构、改善肝功能、抑制T细胞和巨噬细胞的渗透有关。因此，CoPP或基因治疗诱导的HO-1可预防脂肪变性大鼠肝脏的I/R损伤。这些发现为改进新的治疗方法提供了理论基础，这些治疗方法应该会增加可用的供体肝脏的供应，并最终提高肝移植的总体成功。
We examined the effects of upregulation of heme oxygenase-l (HO-1) in steatotic rat liver models of ex vivo cold ischemia/reperfusion (I/R) injury. In the model of ischemia/isolated perfusion, treatment of genetically obese Zucker rats with the HO-1 inducer cobalt protoporphyrin (CoPP) or with adenoviral HO-1 (Ad-HO-1) significantly improved portal venous blood flow, increased bile production, and decreased hepatocyte injury. Unlike in untreated rats or those pretreated with the HO-1 inhibitor zinc protoporphyrin (ZnPP), upregulation of HO-1 by Western blots correlated with amelioration of histologic features of I/R injury. Adjunctive infusion of ZnPP abrogated the beneficial effects of Ad-HO-1 gene transfer, documenting the direct involvement of HO-1 in protection against I/R injury. Following cold ischemia/isotransplantation, HO-1 overexpression extended animal survival from 40% in untreated controls to about 80% after CoPP or Ad-HO-1 therapy. This effect correlated with preserved hepatic architecture, improved liver function, and depressed infiltration by T cells and macrophages. Hence, CoPP- or gene therapy-induced HO-1 prevented I/R injury in steatotic rat livers. These findings provide the rationale for refined new treatments that should increase the supply of usable donor livers and ultimately improve the overall success of liver transplantation.