What is wrong with the vasculature in bronchopulmonary dysplasia?

支气管肺发育不良(BPD)是影响早产儿的一种严重疾病。BPD与肺发育异常和肺动脉高压(PH)有关。尽管已知BPD影响肺血管，而肺血管在发病机制和随后的PH发展中起关键作用，但这种变化在定性和定量上仍不清楚。目前的项目旨在通过新开发的量化方法和血管系统的3D重建的创新组合来缩小这一差距。除了正常的出生后发育，还将研究三种不同BPD模型的肺：高氧小鼠、早产/高氧兔和早产狒狒。早产狒狒模型与人类BPD非常接近，而小鼠和兔子对于未来治疗方法的测试非常重要。肺将通过血管灌流固定，并进行立体量化或3D重建。后者将使用µCT数据集和随后的动脉树光镜分析，或使用整个肺泡的毛细血管网络的电子显微镜3D数据集(连续块面扫描电子显微镜)进行。由于新的方法，我们将能够解决以前无法回答的各种问题。例如，我们将能够将形态变化分配给脉管树的特定分支，这只能通过结合使用µCT和显微镜方法来实现。另一个例子是肺泡毛细血管网的改变。通过一种新的体视学方法(Euler-Poincaré特征)，我们将能够估计肺泡间隔内的毛细血管数量，这有助于识别异常血管发育的性质，并将其与肺泡化的延迟过程联系起来。回答这些和提案中指定的其他问题对于更好地了解BPD的发病机制和开发新的治疗策略是至关重要的。

Bronchopulmonary dysplasia (BPD) is a severe disease affecting immaturely born newborns. BPD is associated with aberrant lung development and pulmonary Hypertension (PH). Although it is known that BPD affects the pulmonary vasculature which is critical for pathogenesis and later PH development, the changes are still unclear both qualitatively and quantitatively. The current Project aims at closing this gap by an innovative combination of newly developed methods of quantification and 3D reconstruction of the vasculature. Besides normal postnatal development, the lungs of three different BPD models will be investigated: hyperoxic mouse, preterm/hyperoxic rabbit and preterm baboon. The preterm baboon model is very close to human BPD whereas the mouse and rabbit are important for future testing of therapeutic approaches. Lungs will be fixed by vascular perfusion and processed for stereological quantification or 3D reconstruction. The latter will be performed using µCT data sets with subsequent light microscopic Analysis of the arterial tree or by using electron microscopic 3D data sets of the capillary network of whole alveoli (Serial block-face scanning electron microscopy). Due to the novel methodology we will be able to address various questions that were previously impossible to be answered. For example we will be able to assign morphological changes to specific branches of the vessel tree which is only possible by the combined µCT and microscopy approach. Another example are the alterations of the alveolar capillary Network. With a new stereological method (Euler-Poincaré characteristic) we will be able to estimate the number of capillaries in the alveolar septa which helps to identify the nature of the aberrant vascular development and to relate it to the delayed process of alveolarization. Answering These and other questions specified in the proposal are essential to better understand BPD pathogenesis and develop new therapeutic strategies.