利用反义寡脱氧核苷酸靶向宿主e -选择素表达作为体内潜在的抗内毒素疗法。

Roy D Goldfarb, C Frank Bennett, Madeline Butler, Thomas Condon, Joseph E Parrillo
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引用次数: 1

摘要

本研究旨在确定反义寡脱氧核苷酸是否会抑制e -选择素的表达,e -选择素介导白细胞在内皮细胞上的粘附,否则会被体内内毒素刺激诱导。本文在猪主动脉内皮细胞中检测了6种与猪e -选择素mRNA结合的反义硫代寡脱氧核苷酸。其中,ISIS9481对肿瘤坏死因子-α +内毒素[脂多糖(LPS)]诱导的e -选择素表达有显著抑制作用。试验用LPS (10 μg/kg)攻毒,用ISIS9481 (10 mg/kg)处理(n = 6)。采用猪主动脉内皮细胞反义失活组(n = 6)和生理盐水组(n = 5)作为对照组(C = 11)。LPS刺激的对照组猪在心脏、肺、肾脏和肝脏中表达e-选择素,而反义处理的猪在这些组织中表达很少e-选择素。心血管数据表明,反义处理可减轻LPS引起的病理生理改变。具体来说,在对照猪中,LPS使心输出量比基线降低32%,增加肺部(+116%)和全身血管阻力(+16%),并产生中性粒细胞减少(从基础51,000增加到LPS后的18,000多形核中性粒细胞(PMN)/μL)。在反义处理的猪中,心输出量仅下降18%,肺血管阻力保持不变,而全身血管阻力与基础值相比下降了37%。LPS作用后3 ~ 4 h, PMN维持在45000 ~ 54000 /μL。这些数据表明,在体外设计和测试与1基因产物相互作用的反义寡脱氧核苷酸可以在体内开发为治疗药物或实验工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting host E-selectin expression by antisense oligodeoxynucleotides as potential antiendotoxin therapy in vivo.

This study sought to determine if antisense oligodeoxynucleotides would inhibit E-selectin expression, which mediates leukocyte adhesion on endothelial cells, otherwise induced by in vivo endotoxin challenge. Six antisense phosphorothioate oligodeoxynucleotides calculated to bind porcine E-selectin mRNA were tested in porcine aortic endothelial cells. One, ISIS9481, exerted significant inhibition of E-selectin expression induced by tumor necrosis factor-α + endotoxin [lipopolysaccharide (LPS)]. Pigs were challenged with LPS (10 μg/kg) and treated with ISIS9481 (10 mg/kg) (n = 6). Two control groups were used, an antisense inactive in porcine aortic endothelial cells (n = 6) and saline (n = 5), and were combined as control (C = 11). Control pigs challenged with LPS expressed E-selectin in heart, lung, kidneys, and liver, whereas antisense-treated pigs expressed little E-selectin in these tissues. Cardiovascular data indicated that antisense treatment attenuated pathophysiological alterations induced by LPS. Specifically, in control pigs, LPS reduced cardiac output 32% from baseline, increased pulmonary (+116%) and systemic vascular resistances (+16%), and generated neutropenia (from 51,000 at basal to 18,000 polymorphonuclear neutrophils (PMN)/μL after LPS). In antisense-treated pigs, cardiac output decreased only 18%, pulmonary vascular resistance remained unchanged, whereas systemic vascular resistance decreased compared with basal values (-37%). PMN counts remained at 45,000-54,000/μL at 3-4 hours after LPS. These data demonstrate that antisense oligodeoxynucleotides, designed and tested in vitro to interact with 1 gene product, can be developed as either therapeutics or experimental tools in vivo.

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Oligonucleotides
Oligonucleotides 生物-生化与分子生物学
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