A novel technique for selective NF-κB inhibition in Kupffer cells: contrary effects in fulminant hepatitis and ischaemia-reperfusion
A novel technique for selective NF-κB inhibition in Kupffer cells: contrary effects in fulminant hepatitis and ischaemia-reperfusion
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DOI：
10.1136/gut.2008.165647
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发表时间：
2009-12-01
期刊：
影响因子：
24.5
通讯作者：
Vollmar, A. M.
中科院分区：
文献类型：
--
作者：
Hoffmann, F.;Sass, G.;Vollmar, A. M.
背景与目的：核转录因子κ B（NF-κ B B）是一种具有广阔应用前景的抗炎治疗靶点。然而，在肝脏中，NF-κ B抑制介导损伤和保护作用。认为结局取决于所处理的肝细胞类型。最近的基因敲除研究集中在肝细胞中NF-κ B的作用，而NF-κ B在枯否细胞中的作用尚未在体内研究。在这里，我们提出了一种新的方法，这可能是适合于临床应用，选择性地针对NF-κ B在枯否细胞和分析在实验模型中的肝injuries.Methods的影响：NF-κ B抑制诱饵寡核苷酸负载在明胶纳米颗粒（D-NPs）和它们的体内分布，通过共聚焦显微镜测定。分别在脂多糖（LPS）、D-半乳糖胺（GalN）/LPS或刀豆球蛋白A（ConA）刺激和部分热缺血及随后再灌注后评价肝损伤、NF-κ B活性、细胞因子水平和凋亡蛋白表达。抑制Kupffer细胞中的NF-κ B可改善GalN/LPS和ConA攻击后的存活率并减少肝损伤。虽然肝组织中的抗凋亡蛋白表达没有减少，但促凋亡因子如cJun N-末端激酶（JNK）被抑制。与此相反，选择性抑制NF-κ B增强再灌注injuries.Conclusions：NF-κ B抑制诱饵寡脱氧核苷酸载明胶纳米粒是一种新的工具，选择性抑制NF-κ B激活在体内枯否细胞。因此，肝损伤可以减少实验性暴发性肝炎，但在缺血再灌注增加。
Background and aims: The transcription factor nuclear factor kappa B (NF-kappa B) has risen as a promising target for anti-inflammatory therapeutics. In the liver, however, NF-kappa B inhibition mediates both damaging and protective effects. The outcome is deemed to depend on the liver cell type addressed. Recent gene knock-out studies focused on the role of NF-kappa B in hepatocytes, whereas the role of NF-kappa B in Kupffer cells has not yet been investigated in vivo. Here we present a novel approach, which may be suitable for clinical application, to selectively target NF-kappa B in Kupffer cells and analyse the effects in experimental models of liver injury.Methods: NF-kappa B inhibiting decoy oligodeoxynucleotides were loaded upon gelatin nanoparticles (D-NPs) and their in vivo distribution was determined by confocal microscopy. Liver damage, NF-kappa B activity, cytokine levels and apoptotic protein expression were evaluated after lipopolysaccharide (LPS), D-galactosamine (GalN)/LPS, or concanavalin A (ConA) challenge and partial warm ischaemia and subsequent reperfusion, respectively.Results: D-NPs were selectively taken up by Kupffer cells and inhibited NF-kappa B activation. Inhibition of NF-kappa B in Kupffer cells improved survival and reduced liver injury after GalN/LPS as well as after ConA challenge. While anti-apoptotic protein expression in liver tissue was not reduced, pro-apoptotic players such as cJun N-terminal kinase (JNK) were inhibited. In contrast, selective inhibition of NF-kappa B augmented reperfusion injury.Conclusions: NF-kappa B inhibiting decoy oligodeoxynucleotide-loaded gelatin nanoparticles is a novel tool to selectively inhibit NF-kappa B activation in Kupffer cells in vivo. Thus, liver injury can be reduced in experimental fulminant hepatitis, but increased at ischaemia-reperfusion.