Maeda Sumiko, Suzuki Satoshi, Suzuki Takashi, Endo Mareyuki, Moriya Takuya, Chida Masayuki, Kondo Takashi, Sasano Hironobu
Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Lab Invest. 2002 Mar;82(3):293-301. doi: 10.1038/labinvest.3780423.
The establishment of a sufficiently wide and functional blood-gas interface is of critical importance in lung development, but development of the intrapulmonary vascular system including alveolar capillary vessels still remains unclear. In this study, we first characterized the structural development of the vascular system in accordance with that of airways in human fetal lungs at the pseudoglandular phase (8, 13, and 16 weeks gestation) by examining the immunohistochemical distribution of CD34 and alpha-smooth muscle actin (SMA). Using double immunohistochemistry and 3-dimensional reconstruction techniques, endothelial cells in the developing lung could be classified into two different types according to the characteristics of their adjacent cells (presence or absence of SMA-positive cells) and their distribution (proximal or distal lung parenchyme). Endothelial cells without SMA-positive cells developed into a capillary network surrounding the budding components of distal airways during the mid-pseudoglandular phase before communicating with proximal vessels. We then examined the immunoreactivity of thrombomodulin and von Willebrand factor (vWF) in endothelial cells. Endothelial cells of the capillary network were mainly positive for vWF during the early gestational stages, but altered their phenotypes to those of mature lungs (vWF negative and thrombomodulin positive) during the terminal sac phase. We subsequently determined the immunohistochemical distribution of vascular endothelial growth factor (VEGF). Epithelial cells of the most distal airways were intensely positive for VEGF. These results suggest that VEGF present in airway epithelial cells is involved in the maturation as well as proliferation of capillary endothelial cells. Epithelial-endothelial interactions during lung development are considered very important in the establishment of the functional blood-gas interface.
建立足够宽且功能正常的气血界面在肺发育中至关重要，但包括肺泡毛细血管在内的肺内血管系统的发育仍不清楚。在本研究中，我们首先通过检测CD34和α平滑肌肌动蛋白（SMA）的免疫组化分布，根据人胎儿肺假腺期（妊娠8、13和16周）气道的发育情况来表征血管系统的结构发育。使用双重免疫组化和三维重建技术，发育中的肺内内皮细胞可根据其相邻细胞的特征（有无SMA阳性细胞）及其分布（近端或远端肺实质）分为两种不同类型。在假腺期中段，没有SMA阳性细胞的内皮细胞发育成围绕远端气道芽生成分的毛细血管网络，然后与近端血管连通。然后我们检测了内皮细胞中血栓调节蛋白和血管性血友病因子（vWF）的免疫反应性。在妊娠早期，毛细血管网络的内皮细胞主要为vWF阳性，但在终末囊期其表型转变为成熟肺的表型（vWF阴性和血栓调节蛋白阳性）。我们随后确定了血管内皮生长因子（VEGF）的免疫组化分布。最远端气道的上皮细胞VEGF呈强阳性。这些结果表明，气道上皮细胞中存在的VEGF参与了毛细血管内皮细胞的成熟和增殖。肺发育过程中的上皮-内皮相互作用在功能性气血界面的建立中被认为非常重要。
