Minimizing oxidative stress by gene delivery of superoxide dismutase accelerates regeneration after transplantation of reduced-size livers in the rat
Minimizing oxidative stress by gene delivery of superoxide dismutase accelerates regeneration after transplantation of reduced-size livers in the rat
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DOI：
10.1002/lt.20632
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发表时间：
2006-04-01
影响因子：
4.6
通讯作者：
Brenner, DA
中科院分区：
文献类型：
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作者：
Lehmann, TG;Luedde, T;Brenner, DA
移植体积较小的肝脏可能会导致高代谢状态和增加氧自由基的产生。由于氧自由基可能导致肝损伤并损害肝再生，我们在减体积肝(RSL)中过表达超氧化物歧化酶(SOD)可以加速RSL的再生并减轻损伤的假说在RSL移植的大鼠模型中得到验证。供体大鼠分别感染表达SOD1腺病毒(Ad.SOD1腺病毒)和表达β-半乳糖酶(Acl.lacZ腺病毒)。72小时后采集肝脏，减至重量的45%，并进行移植。移植后检测肝组织超氧化物歧化酶活性、移植物存活率、组织病理学、AST/ALT释放和胆红素。通过BrdU染色、移植物重量、细胞周期蛋白D1和p21的表达来评估再生情况。在Ad.SOD1处理的肝脏移植物中，与对照组相比，SOD活性增加了三倍。接受Ad.SOD-RSL的患者存活率显著提高(100%比Ad.lacZ-RSL的20%)，AST/ALT峰值水平和胆红素水平分别降低75%和87.5%(P<；0.001)。在组织切片中，肝细胞坏死率从Ad.lacZ处理后的24%降至Ad.SOD处理后的6%(P<；0.001)。再灌注后24小时BrdU染色的细胞增多，1周后肝脏重量增加，表明Ad.SOD处理后再生速度加快。综上所述，SOD1在RSIL中的过表达可防止减体积肝移植物的原发无功能，并加速肝再生。
Transplantation of reduced-size livers may lead to a hypermetabolic state and increased production of oxygen radicals. Since oxygen radicals may cause liver injury and impair liver regeneration, we tested the hypothesis that overexpression of superoxide dismutase (SOD) in reduced-size livers (RSL) would accelerate regeneration and reduce injury in a rat model of transplantation of RSL. Donor rats were infected with adenoviruses either expressing SOD1 (Ad.SOD1) or beta-galactosiclase (Acl.lacZ). Livers were harvested 72 hours later, reduced to 45% of weight, and transplanted. After transplantation, hepatic SOD activity, graft survival, histopathology, AST/ALT release, and bilirubin were examined. Regeneration was evaluated by BrdU-staining, graft weight, and expression of cyclin D1 and p21. In Ad.SOD1-treated livergrafts, SOD activity increased three-fold compared to controls. Survival was dramatically increased in recipients of Ad.SOD1-RSL (100% vs. 20% in Ad.lacZ-RSL), and peak levels of AST/ALT and bilirubin levels were reduced by 75% and 87.5%, respectively (P < 0.001). In histological sections, hepatocyte necrosis decreased from 24% after Ad.lacZ-treatment to 6% after Ad.SOD1-treatment (P < 0.001). Regeneration was also accelerated after Ad.SOD1-treatment as demonstrated by an increase of BrdU-stained cells 24 hours after reperfusion and increased liver weight after 1 week. In conclusion, overexpression of SOD1 in RSIL prevents primary non-function of reduced-size liver grafts and accelerates liver regeneration.