Nuclear factor-κB decoy oligodeoxynucleotides prevent acute lung injury in mice with cecal ligation and puncture-induced sepsis
Nuclear factor-κB decoy oligodeoxynucleotides prevent acute lung injury in mice with cecal ligation and puncture-induced sepsis
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DOI：
10.1124/mol.104.005926
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发表时间：
2005-04-01
影响因子：
3.6
通讯作者：
Gando, S
中科院分区：
文献类型：
--
作者：
Matsuda, N;Hattori, Y;Gando, S
核转录因子-κ B（NF-κ B B）在脓毒症诱导的急性肺损伤的病理生理学中的许多炎症基因的表达中起关键作用。我们研究了在盲肠结扎和穿孔脓毒症小鼠模型中引入合成的具有共有NF-κ B序列的双链寡脱氧核苷酸（ODNs）作为转录因子诱饵是否可以通过抑制参与其病理过程的多个基因的肺表达来预防急性肺损伤。利用日本血凝病毒包膜载体法导入NF-κ B诱饵ODNs。北方印迹分析表明，NF-κ B诱饵ODN的转染，而不是其乱序形式，导致脓毒症诱导的诱导型一氧化氮合酶（iNOS），环氧合酶受体，缓激肽B 1和B 2受体在肺组织中的基因过表达的显着抑制。盲肠结扎和穿刺后，小鼠肺组织学损伤（壁增厚、炎性浸润和出血）、肺血管通透性增加和血气交换障碍均被明确记录。这些变化被强烈消除的NF-κ B诱饵，但不是乱序ODN的引入。与NF-κ B诱饵ODN转染相比，iNOS抑制剂FR 260330对这些组织学和功能紊乱的影响是不利的。我们的研究结果表明，ODN诱饵，作为在体内的竞争对手的转录因子的能力，结合同源识别序列，可能是一种有效的策略，在治疗脓毒性急性肺损伤。
The transcription factor nuclear factor-kappa B ( NF-kappa B) plays a key role in expression of many inflammatory genes responsible for the pathophysiology of sepsis-induced acute lung injury. We investigated whether the introduction of synthetic double-stranded oligodeoxynucleotides (ODNs) with consensus NF-kappa B sequence as transcription factor decoy can prevent acute lung injury with suppression of pulmonary expression of multiple genes involved in its pathological process in a cecal ligation and puncture septic mouse model. NF-kappa B decoy ODNs were introduced with the aid of the hemagglutinating virus of Japan-envelope vector method. Northern blot analysis indicated that transfection of NF-kappa B decoy ODN, but not of its scrambled form, resulted in a significant inhibition of sepsis-induced gene overexpression of inducible nitric-oxide synthase ( iNOS), cyclooxygenase-receptor, and bradykinin B 1 and B 2 receptors in lung tissues. Histological damage in lungs ( wall thickening, inflammatory infiltrate, and hemorrhage), increased pulmonary vascular permeability, and blood gas exchange impairment were clearly documented in mice after cecal ligation and puncture. These changes were strongly eliminated by the introduction of NF-kappa B decoy but not of scrambled ODN. The effects of the iNOS inhibitor FR260330 on these histological and functional derangements compared unfavorably with those of NF-kappa B decoy ODN transfection. Our results suggest that ODN decoy, acting as in vivo competitor for the transcription factor's ability to bind to cognate recognition sequence, may represent an effective strategy in the treatment of septic acute lung injury.