BACKGROUND Bronchopulmonary dysplasia continues to cause important respiratory morbidity throughout life, and new therapies are needed. The common denominator of all BPD cases is preterm birth, however most preclinical research in this area focusses on the effect of hyperoxia or mechanical ventilation. In this study we investigated if and how prematurity affects lung structure and function in neonatal rabbits. METHODS Pups were delivered on either day 28 or day 31. For each gestational age a group of pups was harvested immediately after birth for lung morphometry and surfactant protein B and C quantification. All other pups were hand raised and harvested on day 4 for the term pups and day 7 for the preterm pups (same corrected age) for lung morphometry, lung function testing and qPCR. A subset of pups underwent microCT and dark field imaging on day 0, 2 and 4 for terms and on day 0, 3, 5 and 7 for preterms. RESULTS Preterm pups assessed at birth depicted a more rudimentary lung structure (larger alveoli and thicker septations) and a lower expression of surfactant proteins in comparison to term pups. MicroCT and dark field imaging revealed delayed lung aeration in preterm pups, in comparison to term pups. Preterm birth led to smaller pups, with smaller lungs with a lower alveolar surface area on day 7/day 4. Furthermore, preterm birth affected lung function with increased tissue damping, tissue elastance and resistance and decreased dynamic compliance. Expression of vascular endothelial growth factor (VEGFA) was significantly decreased in preterm pups, however in the absence of structural vascular differences. CONCLUSIONS Preterm birth affects lung structure and function at birth, but also has persistent effects on the developing lung. This supports the use of a preterm animal model, such as the preterm rabbit, for preclinical research on BPD. Future research that focuses on the identification of pathways that are involved in in-utero lung development and disrupted by pre-term birth, could lead to novel therapeutic strategies for BPD.

中文翻译：

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在新生兔模型中，早产会损害产后肺的发育。

背景技术支气管肺发育不良在整个生命中继续引起重要的呼吸道疾病，因此需要新的疗法。所有BPD病例的共同点是早产，但是该领域的大多数临床前研究集中于高氧或机械通气的影响。在这项研究中，我们调查了早产是否以及如何影响新生兔的肺结构和功能。方法幼崽在第28天或第31天分娩。对于每个胎龄，出生后立即收集一组幼崽进行肺形态测定和表面活性剂蛋白B和C定量。人工饲养所有其他幼崽并在第4天收获足月幼崽，在第7天收获早产幼崽（年龄相同）以进行肺形态学，肺功能测试和qPCR。幼仔的子集在足月的第0、2和4天以及早产的第0、3、5和7天接受了microCT和暗场成像。结果与足月幼崽相比，出生时评估的早产幼崽表现出更原始的肺部结构（肺泡更大，隔膜更厚）和表面活性剂蛋白的较低表达。与足月幼崽相比，MicroCT和暗场成像显示早产幼崽的肺通气延迟。早产导致较小的幼崽，第7天/第4天肺较小，肺泡表面积较小。此外，早产会影响肺功能，增加组织阻尼，组织弹性和抵抗力，并降低动态顺应性。在早产幼崽中，血管内皮生长因子（VEGFA）的表达明显降低，但是在没有结构性血管差异的情况下。结论早产会影响出生时的肺结构和功能，但也会对发育中的肺产生持续影响。这支持使用早产动物模型（例如早产兔）进行BPD的临床前研究。未来研究的重点是确定与子宫内肺发育有关的途径并受早产干扰的未来研究，可能会导致BPD的新治疗策略。