Effects of three superoxide dismutase genes delivered with an adenovirus on graft function after transplantation of fatty livers in the rat
Effects of three superoxide dismutase genes delivered with an adenovirus on graft function after transplantation of fatty livers in the rat
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DOI：
10.1097/01.tp.0000065299.29900.17
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发表时间：
2003-07-15
期刊：
影响因子：
6.2
通讯作者：
Thurman, RG
中科院分区：
文献类型：
--
作者：
Lehmann, TG;Wheeler, MD;Thurman, RG
背景氧自由基在器官移植后的缺血/再灌注损伤中起着重要作用，并被内源性自由基清除剂如超氧化物歧化酶（SOD）降解。在大鼠肝移植模型中，通过腺病毒（Ad.SOD1）递送胞质SOD基因来过度表达SOD可减少器官损伤并增加存活率。然而，目前尚不清楚SOD的三种亚型中哪一种提供最大的保护作用。本研究的目的是确定对脂肪肝移植后缺血/再灌注损伤具有最高有效性的同种型，这是特别容易的。供体大鼠在收获前通过灌胃给予乙醇以诱导脂肪变性肝脏。用表达编码细菌β-半乳糖苷酶的基因lacZ（Ad. lacZ）、Ad.SOD1、Ad.SOD2（线粒体同种型）或Ad.SOD3（细胞外同种型）的腺病毒感染一些供体。观察移植后肝组织SOD活性、存活率、组织病理学、转氨酶、核因子（NF）-kappaB、IkappaB激酶、JNK和TNF-α的活性。Ad.SOD1治疗增加了存活率，减弱了转氨酶的释放，减少了坏死，而Ad.SOD3没有保护作用。Ad.SOD2的保护性不如Ad.SOD1。Ad.SOD1降低了NF-κ B的活化，减弱了JNK活性，并降低了TNF-α活性。Ad.SOD2治疗导致较低的激酶、TNF-α和NF-κ B活性，但不如Ad.SOD1有效。IkappaB激酶活性不受影响。这项研究表明，胞质SOD是最有效的SOD亚型，以保护移植肝失败，这可能与降低NF-κ B和JNK活性，因为减少氧源性自由基的产生。
Background. Oxygen-derived free radicals play a central role in ischemia/reperfusion injury after organ transplantation and are degraded by endogenous radical scavengers such as superoxide dismutase (SOD). Overexpression of SOD by delivery of the cytosolic SOD gene with an adenovirus (Ad.SOD1) decreases organ injury and increases survival in a rat model of liver transplantation. However, it is unclear which of the three isoforms of SOD provides the most protective effect. The purpose of this study was to identify the isoform with the highest effectiveness against ischemia/reperfusion injury after transplantation of fatty livers, which are particularly susceptible.Methods. Donor rats were given ethanol by gavage before harvest to induce steatotic livers. Some of the donors were infected with adenoviruses expressing either the gene lacZ encoding bacterial beta-galactosidase (Ad.lacZ), Ad.SOD1, Ad.SOD2 (mitochondrial isoform), or Ad.SOD3 (extracellular isoform). After transplantation, SOD activity in liver, survival, histopathology, transaminases, and activation of nuclear factor (NF)-kappaB, IkappaB kinase, Jun-N-terminal kinase (JNK), and tumor necrosis factor (TNF)-alpha were evaluated.Results. Ad.SOD1 treatment increased survival, blunted transaminase release, and reduced necrosis, whereas Ad.SOD3 had no protective effect. Ad.SOD2 was not as protective as Ad.SOD1. Ad.SOD1 reduced the activation of NF-kappaB, blunted JNK activity, and reduced TNF-alpha activity. Ad.SOD2 treatment resulted in lower kinase, TNF-alpha, and NF-kappaB activities but was not as effective as Ad.SOD1. IkappaB kinase activity was not affected.Conclusion. This study demonstrates that cytosolic SOD represents the most effective isoform of SOD to protect transplanted livers from failure; this may be related to lowered NF-kappaB and JNK activities because of reduced oxygen-derived radical production.