Le Cras Timothy D, Hardie William D, Fagan Karen, Whitsett Jeffrey A, Korfhagen Thomas R
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Am J Physiol Lung Cell Mol Physiol. 2003 Nov;285(5):L1046-54. doi: 10.1152/ajplung.00045.2003. Epub 2003 Aug 1.
Pulmonary vascular disease plays a major role in morbidity and mortality in infant and adult lung diseases in which increased levels of transforming growth factor (TGF)-alpha and its receptor EGFR have been associated. The aim of this study was to determine whether overexpression of TGF-alpha disrupts pulmonary vascular development and causes pulmonary hypertension. Lung-specific expression of TGF-alpha in transgenic mice was driven with the human surfactant protein (SP)-C promoter. Pulmonary arteriograms and arterial counts show that pulmonary vascular development was severely disrupted in TGF-alpha mice. TGF-alpha mice developed severe pulmonary hypertension and vascular remodeling characterized by abnormally extensive muscularization of small pulmonary arteries. Pulmonary vascular development was significantly improved and pulmonary hypertension and vascular remodeling were prevented in bi-transgenic mice expressing both TGF-alpha and a dominant-negative mutant EGF receptor under the control of the SP-C promoter. Vascular endothelial growth factor (VEGF-A), an important angiogenic factor produced by the distal epithelium, was decreased in the lungs of TGF-alpha adults and in the lungs of infant TGF-alpha mice before detectable abnormalities in pulmonary vascular development. Hence, overexpression of TGF-alpha caused severe pulmonary vascular disease, which was mediated through EGFR signaling in distal epithelial cells. Reductions in VEGF may contribute to the pathogenesis of pulmonary vascular disease in TGF-alpha mice.
肺血管疾病在婴幼儿和成人肺部疾病的发病和死亡中起主要作用，其中转化生长因子（TGF）-α及其受体表皮生长因子受体（EGFR）水平升高与之相关。本研究的目的是确定TGF-α的过表达是否会破坏肺血管发育并导致肺动脉高压。用人类表面活性蛋白（SP）-C启动子驱动TGF-α在转基因小鼠中的肺特异性表达。肺血管造影和动脉计数显示，TGF-α小鼠的肺血管发育严重受损。TGF-α小鼠出现严重的肺动脉高压和血管重塑，其特征是小肺动脉异常广泛的肌化。在SP-C启动子控制下同时表达TGF-α和显性负性突变型表皮生长因子受体的双转基因小鼠中，肺血管发育得到显著改善，肺动脉高压和血管重塑得到预防。血管内皮生长因子（VEGF-A）是由远端上皮产生的一种重要血管生成因子，在TGF-α成年小鼠的肺以及肺血管发育出现可检测到的异常之前的幼年TGF-α小鼠的肺中均减少。因此，TGF-α的过表达导致严重的肺血管疾病，这是通过远端上皮细胞中的EGFR信号传导介导的。VEGF的减少可能有助于TGF-α小鼠肺血管疾病的发病机制。
