Lung overexpression of the vascular endothelial growth factor gene induces pulmonary edema
Lung overexpression of the vascular endothelial growth factor gene induces pulmonary edema
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DOI：
10.1165/ajrcmb.22.6.3779
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发表时间：
2000-06-01
影响因子：
6.4
通讯作者：
Crystal, RG
中科院分区：
文献类型：
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作者：
Kaner, RJ;Ladetto, JV;Crystal, RG
我们推测，已知的血管生成介质血管内皮生长因子(VECF)在肺中表达，并能够引起皮肤局部水肿，如果过度表达，可能会引起肺水肿。为了验证这一假说，我们建立了一种体内VECF在肺内过表达的模型，该模型是基于E1(-)腺病毒载体(AdVEGF165)将VECF165互补DNA运送到呼吸道上皮细胞。经气管内注射AdVECF165(10(9)个空斑形成单位[PFU])给C57BI/6小鼠，Northern分析显示肺组织中VEGF信使RNA的表达增加。酶联免疫吸附试验证实1~10天肺组织中有高表达的血管内皮生长因子蛋白。气管内给予AdVEGF165后，肺湿/干重比随时间呈剂量依赖性增加，肺组织学表现为广泛的肺泡内水肿，伊文思蓝染色和[I-131]白蛋白通透性测定显示肺毛细血管通透性显著增加。为了证实这些观察的特异性，小鼠被鼻腔注射表达截短的VEGF受体Flt-1(Adsflt)的腺病毒载体(Adsflt)，Adsflt(109pfu)预处理完全消除了由AdVEGF165引起的肺湿/干重比的增加，而相同的带有无关转基因的腺病毒载体对随后的AdVEGF165诱导的肺水肿没有影响。综上所述，这些数据提示，肺组织中血管内皮生长因子的过度表达可能是急性肺损伤早期肺血管通透性增加的机制之一。
We hypothesized that the angiogenic mediator, vascular endothelial growth factor (VECF), known to be expressed in the lung and to be capable of inducing local edema in skin, might evoke the development of lung edema if expressed in excess amounts. To test this hypothesis, we developed an in vivo model of VECF overexpression in the lung on the basis of delivery to the respiratory epithelium of the VECF165 complementary DNA by an E1(-) adenovirus vector (AdVEGF165). Administration of AdVECF165 by the intratracheal route (10(9) plaque-forming units [pfu]) to C57BI/6 mice showed increased expression of VEGF messenger RNA in lung tissue by Northern analysis. Overexpression of VEGF protein in the lung at Days 1 to 10 was confirmed by enzyme-linked immunosorbent assay. Intratracheal administration of AdVEGF165 resulted in a dose-dependent increase in lung wet/dry weight ratios over time, lung histology showed widespread intraalveolar edema, and pulmonary capillary permeability was significantly increased as quantified by the Evans blue dye assay and [I-131]albumin permeability. To confirm the specificity of these observations, mice were pretreated with intranasal administration of an adenovirus vector expressing a truncated soluble form of the VEGF receptor flt-1 (Adsflt), Adsflt (109 pfu) pretreatment completely abrogated the increased lung wet/dry weight ratio caused by AdVEGF165 administration, whereas an identical adenovirus vector with an irrelevant transgene had no effect upon subsequent AdVEGF165-induced pulmonary edema. Together, these data suggest that overexpression of VEGF in the lung may be one mechanism of increased pulmonary vascular permeability in the early stages of acute lung injury.