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首页> 外文期刊>American Journal of Physiology >Therapeutic effect of in vivo transfection of transcription factor decoy to NF-kappaB on septic lung in mice.
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Therapeutic effect of in vivo transfection of transcription factor decoy to NF-kappaB on septic lung in mice.

机译：转录因子诱饵体内转染至NF-κB对小鼠败血性肺的治疗作用。

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摘要

Nuclear factor-kappaB (NF-kappaB) plays a key role in regulating expression of several genes involved in the pathophysiology of endotoxic shock. We investigated whether in vivo introduction of synthetic double-stranded DNA with high affinity for the NF-kappaB binding site could block expression of genes mediating pulmonary vascular permeation and thereby provide effective therapy for septic lung failure. Endotoxic shock was induced by an intravenous injection of 10 mg/kg Escherichia coli endotoxin in mice. We introduced NF-kappaB decoy oligodeoxynucleotide (ODN) in vivo 1 h after endotoxic shock by using a gene transfer kit. At 10 h, blood samples were collected for measurement of histamine and for blood-gas analysis. Gene and protein expression levels of target molecules were determined by means of Northern and Western blot analyses, respectively. The transpulmonary flux of (125)I-labeled albumin was used as an index of lung vascular permeability. Administration of endotoxin caused marked increases inplasma histamine and gene and protein expressions of histidine decarboxylase, histamine H(1) receptors, and inducible nitric oxide synthase in lung tissues. Elevated lung vascular permeability was also found. Blood-gas analysis showed concurrent decreases in arterial Po(2), Pco(2), and pH. All of these events induced by endotoxin were significantly inhibited by transfection of NF-kappaB decoy ODN but not by its mutated (scrambled) form (used as a control). Our results indicate for the first time the potential usefulness of NF-kappaB decoy ODN for gene therapy of endotoxic shock.
机译：核因子-κB（NF-kappaB）在调节与内毒素休克的病理生理学有关的几个基因的表达中起关键作用。我们调查了体内引入对NF-kappaB结合位点具有高亲和力的合成双链DNA是否可以阻断介导肺血管渗透的基因的表达，从而为败血性肺衰竭提供有效的治疗方法。通过在小鼠中静脉内注射10 mg / kg大肠杆菌内毒素诱导内毒素休克。我们使用基因转移试剂盒在内毒素休克后1小时体内引入了NF-κB诱饵寡聚脱氧核苷酸（ODN）。在10小时时，收集血样用于组胺的测量和血气分析。分别通过Northern和Western印迹分析确定靶分子的基因和蛋白质表达水平。 （125）I标记的白蛋白的经肺通量被用作肺血管通透性的指标。内毒素的施用引起肺组织中血浆组胺和组氨酸脱羧酶，组胺H（1）受体和诱导型一氧化氮合酶的基因和蛋白质表达显着增加。还发现肺血管通透性升高。血气分析显示动脉Po（2），Pco（2）和pH值同时降低。内毒素诱导的所有这些事件均通过转染NF-kappaB诱饵ODN而受到显着抑制，但不受其突变（加扰）形式（用作对照）的抑制。我们的结果首次表明了NF-κB诱饵ODN在内毒素休克基因治疗中的潜在用途。

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