Institute of Functional and Applied Anatomy and.
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research (DZL), Hannover, Germany.
Am J Respir Cell Mol Biol. 2021 Jul;65(1):81-91. doi: 10.1165/rcmb.2021-0004OC.
Bronchopulmonary dysplasia (BPD), the most common sequela of preterm birth, is a severe disorder of the lung that is often associated with long-lasting morbidity. A hallmark of BPD is the disruption of alveolarization, whose pathogenesis is incompletely understood. Here, we tested the vascular hypothesis that disordered vascular development precedes the decreased alveolarization associated with BPD. Neonatal mouse pups were exposed to 7, 14, or 21 days of normoxia (21% O) or hyperoxia (85% O) with = 8-11 for each group. The right lungs were fixed by vascular perfusion and investigated by design-based stereology or three-dimensional reconstruction of data sets obtained by serial block-face scanning EM. The alveolar capillary network of hyperoxia-exposed mice was characterized by rarefaction, partially altered geometry, and widening of capillary segments as shown by three-dimensional reconstruction. Stereology revealed that the development of alveolar epithelium and capillary endothelium was decreased in hyperoxia-exposed mice; however, the time course of these effects was different. That the surface area of the alveolar epithelium was smaller in hyperoxia-exposed mice first became evident at Day 14. In contrast, the surface area of the endothelium was reduced in hyperoxia-exposed mouse pups at Day 7. The thickness of the air-blood barrier decreased during postnatal development in normoxic mice, whereas it increased in hyperoxic mice. The endothelium and the septal connective tissue made appreciable contributions to the thickened septa. In conclusion, the present study provides clear support for the idea that the stunted alveolarization follows the disordered microvascular development, thus supporting the vascular hypothesis of BPD.
支气管肺发育不良（BPD）是早产儿最常见的后遗症，是一种严重的肺部疾病，常伴有长期发病。BPD 的一个标志是肺泡化的破坏，其发病机制尚不完全清楚。在这里，我们测试了血管假说，即血管发育障碍先于与 BPD 相关的肺泡化减少。将新生小鼠暴露于常氧（21% O）或高氧（85% O）7、14 或 21 天，每组有 8-11 只。用血管灌注固定右肺，并通过基于设计的体视学或通过连续块面扫描 EM 获得的数据集的三维重建进行研究。高氧暴露小鼠的肺泡毛细血管网络的特征是稀疏、部分改变的几何形状和毛细血管段变宽，这可以通过三维重建显示。体视学显示，高氧暴露小鼠的肺泡上皮和毛细血管内皮发育减少；然而，这些效应的时间过程不同。高氧暴露小鼠的肺泡上皮表面积较小首先在第 14 天变得明显。相比之下，高氧暴露小鼠的内皮表面积在第 7 天减少。在正常氧小鼠中，空气-血液屏障在出生后发育过程中变薄，而在高氧小鼠中则变厚。内皮和隔结缔组织对增厚的隔作出了可观的贡献。总之，本研究清楚地支持了这样的观点，即发育不良的肺泡化紧随紊乱的微血管发育之后，从而支持了 BPD 的血管假说。
