The association of autophagy with polyethylenimine-induced cytotoxity in nephritic and hepatic cell lines
The association of autophagy with polyethylenimine-induced cytotoxity in nephritic and hepatic cell lines
复制标题
肾细胞和肝细胞系中自噬与聚乙烯亚胺诱导的细胞毒性的关系
DOI：
10.1016/j.biomaterials.2011.07.047
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发表时间：
2011-11-01
期刊：
影响因子：
14
通讯作者：
Chen, Hongzhuan
中科院分区：
文献类型：
--
作者：
Gao, Xiaoling;Yao, Lei;Chen, Hongzhuan
聚乙烯亚胺（PEI）是实验性基因转移/治疗方案中最有效和广泛使用的阳离子大分子之一。然而，PEI的进一步临床应用在很大程度上受到其细胞毒性的阻碍。在这里，我们进行了PEI诱导的细胞毒性在肝和肾细胞系的机制的基本调查。研究表明，除了坏死和凋亡外，自噬与PEI诱导的细胞毒性明显相关，并有助于加重细胞损伤。具体而言，在PEI诱导的细胞毒性的早期阶段（3小时），自噬主要与溶酶体损伤相关，但在后期阶段（24小时恢复后），自噬主要与线粒体损伤相关。调节Rab 5、Rab 7的表达和抑制网格蛋白介导的内吞作用对自噬体的形成有显著影响，提示内质网溶酶体转运途径尤其是网格蛋白介导的内吞作用至少部分促进了PEI诱导的自噬。由于PEI诱导的自噬在其细胞毒性中发挥了重要作用，因此强烈建议设计基于PEI的基因载体，以避免内溶酶体转运途径。(C)2011爱思唯尔有限公司保留所有权利。
Polyethylenimine (PEI) is one of the most effective and widely used cationic macromolecules in experimental gene transfer/therapy protocols. However, the further clinical application of PEI is largely impeded by its cytotoxicity. Here we performed a fundamental investigation on the mechanism of PEI-induced cytotoxicity in both hepatic and nephritic cell lines. It was demonstrated that besides necrosis and apoptosis, autophagy was apparently associated with PEI-induced cytotoxicity and contributed to aggravated cell damage. Specifically, at the early stage (3 h) of PEI-induced cytotoxicity, autophagy was mainly correlated with lysosome damage, but in the later phase (after a 24-h recovery), autophagy was mainly related with mitochondrial injury. Modulation of Rab5, Rab7 expression and inhibition of clathrin-mediated endocytosis pathway significantly affected the formation of autophagosome, which suggested that the endolysosome transport pathway especially the clathrin-mediated endocytosis at least partly facilitated PEI-induced autophagy. As PEI-induced autophagy played a causative role in its cytotoxicity, it's highly recommended to design PEI-based gene-carriers that could avoid the endolysosome transport pathway. (C) 2011 Elsevier Ltd. All rights reserved.