Le Cras T D, Hardie W D, Deutsch G H, Albertine K H, Ikegami M, Whitsett J A, Korfhagen T R
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229, USA.
Am J Physiol Lung Cell Mol Physiol. 2004 Oct;287(4):L718-29. doi: 10.1152/ajplung.00084.2004. Epub 2004 Apr 16.
Clinical studies have associated increased transforming growth factor (TGF)-alpha and EGF receptor with lung remodeling in diseases including bronchopulmonary dysplasia (BPD). BPD is characterized by disrupted alveolar and vascular morphogenesis, inflammation, and remodeling. To determine whether transient increases in TGF-alpha are sufficient to disrupt postnatal lung morphogenesis, we utilized neonatal transgenic mice conditionally expressing TGF-alpha. Expression of TGF-alpha from postnatal days 3 to 5 disrupted postnatal alveologenesis, causing permanent enlargement of distal air spaces in neonatal and adult mice. Lung volume-to-body weight ratios and lung compliance were increased in adult TGF-alpha transgenic mice, whereas tissue and airway elastance were reduced. Elastin fibers in the alveolar septae were fragmented and disorganized. Pulmonary vascular morphogenesis was abnormal in TGF-alpha mice, with attenuated and occasionally tortuous arterial branching. The ratios of right ventricle weight to left ventricle plus septal weight were increased in TGF-alpha mice, indicating pulmonary hypertension. Electron microscopy showed gaps in the capillary endothelium and extravasation of erythrocytes into the alveolar space of TGF-alpha mice. Hemorrhage and inflammatory cells were seen in distal air spaces at 1 mo of age. In adult TGF-alpha mice, alveolar remodeling, nodules, proteinaceous deposits, and inflammatory cells were seen. Immunostaining for pro-surfactant protein C showed that type II cells were abundant in the nodules, as well as neutrophils and macrophages. Trichrome staining showed that pulmonary fibrosis was minimal, apart from areas of nodular remodeling in adult TGF-alpha mice. Transient induction of TGF-alpha during early alveologenesis permanently disrupted lung structure and function and caused chronic lung disease.
临床研究表明，在包括支气管肺发育不良（BPD）在内的疾病中，转化生长因子（TGF）-α和表皮生长因子受体的增加与肺重塑有关。BPD的特征是肺泡和血管形态发生紊乱、炎症和重塑。为了确定TGF-α的短暂增加是否足以破坏出生后肺的形态发生，我们利用了条件性表达TGF-α的新生转基因小鼠。出生后第3至5天TGF-α的表达破坏了出生后肺泡形成，导致新生小鼠和成年小鼠远端气腔永久性扩大。成年TGF-α转基因小鼠的肺体积与体重比和肺顺应性增加，而组织和气道弹性降低。肺泡间隔中的弹性纤维破碎且排列紊乱。TGF-α小鼠的肺血管形态发生异常，动脉分支变细且偶尔迂曲。TGF-α小鼠的右心室重量与左心室加室间隔重量的比值增加，表明存在肺动脉高压。电子显微镜显示TGF-α小鼠的毛细血管内皮有间隙，红细胞渗入肺泡腔。在1月龄时，远端气腔可见出血和炎症细胞。在成年TGF-α小鼠中，可见肺泡重塑、结节、蛋白质沉积和炎症细胞。前表面活性蛋白C的免疫染色显示，结节中II型细胞丰富，还有中性粒细胞和巨噬细胞。三色染色显示，除成年TGF-α小鼠的结节重塑区域外，肺纤维化程度较轻。早期肺泡形成过程中TGF-α的短暂诱导永久性地破坏了肺结构和功能，并导致慢性肺病。
