Protection against TNFα-dependent liver toxicity by intraperitoneal liposome delivered DsiRNA targeting TNFα in vivo.
Protection against TNFα-dependent liver toxicity by intraperitoneal liposome delivered DsiRNA targeting TNFα in vivo.
复制标题
DOI：
10.1016/j.jconrel.2011.10.034
复制
发表时间：
2012-06-10
期刊：
影响因子：
--
通讯作者：
Cantin EM
中科院分区：
文献类型：
--
作者：
Lundberg P;Yang HJ;Jung SJ;Behlke MA;Rose SD;Cantin EM
肿瘤坏死因子α（TNFα）是一种经典的促炎细胞因子，参与了包括病毒性脑炎在内的多种自身免疫性和炎性疾病的发病机制。因此，作为TNFα的主要生产者的巨噬细胞是体内RNA干扰（RNAi）介导的TNFα下调的有吸引力的靶标。然而，RNAi技术在体内模型中的应用存在障碍，包括RNA双链体在血浆中的快速降解、向靶细胞群体的递送不足以及与合成RNA和载体化合物的静脉内施用相关的毒性。我们利用巨噬细胞的吞噬能力，通过腹腔内给予脂质-DsiRNA复合物来递送靶向TNFα的Dicer底物小干扰RNA（DsiRNAs）（DsiTNFα），该复合物可被腹腔巨噬细胞和其他吞噬细胞有效摄取。我们报道了DsiTNFα-脂质复合物经腹腔给药改变了急性脓毒症模型的疾病结局。下调腹膜CD 11b+单核细胞中的TNFα可减轻C57 BL/6小鼠的肝损伤，并显著延迟低剂量LPS + D-半乳糖胺（D-GalN）处理小鼠的急性死亡率。
Tumor necrosis factor alpha (TNFα) is a classic proinflammatory cytokine implicated in the pathogenesis of several autoimmune and inflammatory diseases including viral encephalitis. Macrophages being major producers of TNFα are thus attractive targets for in vivo RNA interference (RNAi) mediated down regulation of TNFα. The application of RNAi technology to in vivo models however presents obstacles, including rapid degradation of RNA duplexes in plasma, insufficient delivery to the target cell population and toxicity associated with intravenous administration of synthetic RNAs and carrier compounds. We exploited the phagocytic ability of macrophages for delivery of Dicer-substrate small interfering RNAs (DsiRNAs) targeting TNFα (DsiTNFα) by intraperitoneal administration of lipid-DsiRNA complexes that were efficiently taken up by peritoneal macrophages and other phagocytic cells. We report that DsiTNFα-lipid complexes delivered intraperitoneally altered the disease outcome in an acute sepsis model. Down-regulation of TNFα in peritoneal CD11b+ monocytes reduced liver damage in C57BL/6 mice and significantly delayed acute mortality in mice treated with low dose LPS plus D-galactosamine (D-GalN).
登录
查看更多内容
影响因子：
12.4
作者：
Howard, Kenneth A.;Rahbek, Ulrik L.;Kjems, Jorgen
通讯作者：
Kjems, Jorgen
影响因子：
3.9
作者：
Coumoul, Xavier;Deng, Chu-Xia
通讯作者：
Deng, Chu-Xia
影响因子：
14.9
作者：
Rose SD;Kim DH;Amarzguioui M;Heidel JD;Collingwood MA;Davis ME;Rossi JJ;Behlke MA
通讯作者：
Behlke MA
DOI：
10.1073/pnas.76.11.5939
发表时间：
1979-01-01
影响因子：
11.1
作者：
GALANOS, C;FREUDENBERG, MA;REUTTER, W
通讯作者：
REUTTER, W
影响因子：
12.4
作者：
Robbins, Marjorie;Judge, Adam;MacLachlan, Ian
通讯作者：
MacLachlan, Ian