Le Cras T D, Spitzmiller R E, Albertine K H, Greenberg J M, Whitsett J A, Akeson A L
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, OH 45229-3039, USA.
Am J Physiol Lung Cell Mol Physiol. 2004 Jul;287(1):L134-42. doi: 10.1152/ajplung.00050.2004. Epub 2004 Mar 19.
To determine whether increased levels of VEGF disrupt postnatal lung formation or function, conditional transgenic mice in which VEGF 164 expression was enhanced in respiratory epithelial cells were produced. VEGF expression was induced in the lungs of VEGF transgenic pups with doxycycline from postnatal day 1 through 2 and 6 wk of age. VEGF levels were higher in bronchoalveolar lavage fluid (BALF) and lung homogenates of VEGF transgenic mice compared with endogenous VEGF levels in controls. Neonatal mortality was increased by 50% in VEGF transgenic mice. Total protein content in BALF was elevated in VEGF transgenic mice. Surfactant protein B protein expression was unaltered in VEGF transgenic mice. Although postnatal alveolar and vascular development were not disrupted by VEGF expression, VEGF transgenic mice developed pulmonary hemorrhage, alveolar remodeling, and macrophage accumulation as early as 2 wk of age. Electron microscopy demonstrated abnormal alveolar capillary endothelium in the VEGF transgenic mice. In many locations, the endothelium was discontinuous with segments of attenuated endothelial cells. Large numbers of hemosiderin-laden macrophages and varying degrees of emphysema were observed in adult VEGF transgenic mice. Overexpression of VEGF in the neonatal lung increased infant mortality and caused pulmonary hemorrhage, hemosiderosis, alveolar remodeling, and inflammation.
为了确定血管内皮生长因子（VEGF）水平升高是否会破坏出生后肺的形成或功能，我们构建了条件转基因小鼠，其呼吸上皮细胞中VEGF 164的表达增强。从出生后第1天到2周龄以及6周龄，用强力霉素诱导VEGF转基因幼崽肺中的VEGF表达。与对照组的内源性VEGF水平相比，VEGF转基因小鼠的支气管肺泡灌洗液（BALF）和肺匀浆中的VEGF水平更高。VEGF转基因小鼠的新生儿死亡率增加了50%。VEGF转基因小鼠BALF中的总蛋白含量升高。VEGF转基因小鼠中表面活性蛋白B的蛋白表达未改变。尽管出生后肺泡和血管发育未因VEGF表达而受到破坏，但VEGF转基因小鼠早在2周龄时就出现了肺出血、肺泡重塑和巨噬细胞积聚。电子显微镜显示VEGF转基因小鼠的肺泡毛细血管内皮异常。在许多部位，内皮是不连续的，有部分内皮细胞变薄。在成年VEGF转基因小鼠中观察到大量含铁血黄素的巨噬细胞和不同程度的肺气肿。新生儿肺中VEGF的过度表达增加了婴儿死亡率，并导致肺出血、含铁血黄素沉着、肺泡重塑和炎症。
