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肺上皮紧密连接通透性的短暂增加:全氟化学液体增强肺转基因表达的一种额外机制。

Transient increase in lung epithelial tight junction permeability: an additional mechanism for enhancement of lung transgene expression by perfluorochemical liquids.

作者信息

Weiss Daniel J, Beckett Travis, Bonneau Laura, Young Jadrien, Kolls Jay K, Wang Guoshun

机构信息

Pulmonary and Critical Care, Vermont Lung Center, University of Vermont School of Medicine, Burlington, Vermont 05405-0075, USA.

出版信息

Mol Ther. 2003 Dec;8(6):927-35. doi: 10.1016/j.ymthe.2003.09.003.

Abstract

Intratracheal instillation of perfluorochemical (PFC) liquids enhances lung epithelial transgene expression by improved vector propulsion throughout lung airways. We now demonstrate that PFC liquids also facilitate gene transfer by increasing transepithelial permeability. Apical application of PFC liquid to well-differentiated human airway epithelial cells resulted in a transient decrease in transepithelial resistance peaking approximately 2 h after PFC liquid administration and returning to normal approximately 24 h later. The permeability change was sufficient to enhance access of apically applied 100-nm latex beads and adenoviral vectors to the basolateral side of the culture. Adenovirus-mediated gene expression was concurrently enhanced. Following intratracheal instillation of PFC liquid into mouse lungs, tight junction permeability, as assessed by electron microscopic evaluation of lanthanum deposition, was increased with peak effect between 6 h and 1 day after instillation. Importantly, alveolar-capillary permeability remained unchanged with the treatment. Administration of PFC liquid 6 h or 1 day, but not 3 days, prior to instillation of a recombinant adenovirus vector enhanced gene expression comparable to that observed with concurrent administration of PFC liquid and vector. We conclude that transient increase in epithelial permeability after PFC liquid administration contributes to the enhancement of adenovirus vector-mediated gene expression in lung epithelium.

摘要

经气管内滴注全氟化合物(PFC)液体可通过改善载体在整个肺气道中的推进来增强肺上皮转基因表达。我们现在证明,PFC液体还可通过增加跨上皮通透性来促进基因转移。将PFC液体顶端应用于分化良好的人气道上皮细胞,导致跨上皮电阻短暂降低,在给予PFC液体后约2小时达到峰值,约24小时后恢复正常。通透性变化足以增强顶端应用的100纳米乳胶珠和腺病毒载体进入培养物基底外侧的能力。腺病毒介导的基因表达同时增强。将PFC液体经气管内滴注到小鼠肺中后,通过镧沉积的电子显微镜评估,紧密连接通透性增加,滴注后6小时至1天达到峰值效应。重要的是,治疗后肺泡-毛细血管通透性保持不变。在滴注重组腺病毒载体前6小时或1天给予PFC液体,但不是3天,可增强基因表达,与同时给予PFC液体和载体时观察到的情况相当。我们得出结论,给予PFC液体后上皮通透性的短暂增加有助于增强腺病毒载体介导的肺上皮基因表达。

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