Cytoprotective Effects of Human Interleukin-10 Gene Transfer Against Necrosis and Apoptosis Induced by Hepatic Cold Ischemia/Reperfusion Injury
Cytoprotective Effects of Human Interleukin-10 Gene Transfer Against Necrosis and Apoptosis Induced by Hepatic Cold Ischemia/Reperfusion Injury
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DOI：
10.1016/j.jss.2009.03.004
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发表时间：
2009-11-01
影响因子：
2.2
通讯作者：
Li, Dong-Bo
中科院分区：
文献类型：
--
作者：
Li, Jie-qun;Qi, Hai-zhi;Li, Dong-Bo
背景肝细胞凋亡和坏死在肝缺血再灌注损伤中起重要作用。白细胞介素10（IL-10）是一种Th 2型细胞因子，通过抑制促炎细胞因子的产生来调节炎症反应。本研究集中于细胞保护和抗凋亡途径，以评估人IL-10（hIL-10）的基因转导可能使移植物抵抗冷I/R损伤的机制。将编码hIL-10或β-半乳糖苷酶（LacZ）的腺病毒通过上级肠系膜静脉注射到预期的供体动物中。在转导后48小时收获供体肝脏，并在移植前在4 ° C乳酸林格氏溶液中储存12小时。评估移植物存活率、肝功能、坏死和凋亡程度以及凋亡网络分子。Ad-hIL-10预处理可显著延长移植肝的存活时间，改善肝功能，保护肝细胞的完整性和结构，抑制肝细胞凋亡和坏死。此外，Ad-hIL-10预处理可减少线粒体细胞色素c向胞浆的释放，降低caspase-3的活性，同时上调抗氧化剂HO-1和抗凋亡分子Bcl-2的表达。腺病毒介导的hIL-10基因转染可通过减少肝细胞坏死和凋亡减轻冷I/R损伤。细胞保护作用的潜在机制可能至少与抑制caspase-3活性和线粒体细胞色素c释放以及上调抗凋亡（Bcl-2）和抗氧化（HO-1）分子有关。(C)2009 Elsevier Inc. All rights reserved.
Background. Apoptosis as well as necrosis may play an important role in hepatic ischemia/reperfusion (I/R) injury. Interleukin 10 (IL-10), a Th2 type cytokine, modulates inflammatory responses by inhibiting the production of proinflammatory cytokines. The study focused on cytoprotective and antiapoptotic pathways to assess mechanisms by which gene transduction of human IL-10 (hIL-10) may renders grafts resistant to the cold I/R injury.Materials and Methods. Adenoviruses encoding hIL-10 or beta-galactosidase (LacZ) were injected via the superior mesenteric vein into prospective donor animals. The donor liver was harvested 48h after transduction, and stored for 12h at 4 degrees C lactated Ringer's solution prior to being transplanted. Graft survival, liver function, the degree of necrosis and apoptosis, and the molecules of apoptotic networks were assessed.Results. Ad-hIL-10 pretreatment significantly prolonged the survival of liver grafts by improving liver function, preserving hepatocyte integrity and architecture, and depressing intrahepatic apoptosis and necrosis. In addition, Ad-hIL-10 pretreatment diminished the release of cytochrome c from mitochondria into cytoplasm and caspase-3 activity, with simultaneous up-regulated of antioxidant HO-1 and anti-antiapoptotic Bcl-2 molecules.Conclusion. Adenoviral gene transfer of hIL-10 ameliorated cold I/R injury by decreasing hepatic necrosis and apoptosis. The underlying mechanism of cytoprotective effects may at least be involved with the inhibition of caspase-3 activity and mitochondrial cytochrome c release, and the up-regulation of antiapoptotic (Bcl-2) and antioxidant (HO-1) molecules. (C) 2009 Elsevier Inc. All rights reserved.