Department of Intensive Care Medicine and Neonatology, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland.
Children's Research Centre, University Children's Hospital Zurich, Steinwiesstrasse 75, 8032, Zurich, Switzerland.
J Transl Med. 2019 Mar 18;17(1):91. doi: 10.1186/s12967-019-1843-1.
Hyperoxia-induced bronchopulmonary dysplasia (BPD) models are essential for better understanding and impacting on long-term pulmonary, cardiovascular, and neurological sequelae of this chronic disease. Only few experimental studies have systematically compared structural alterations with lung function measurements.
In three separate and consecutive series, Sprague-Dawley infant rats were exposed from day of life (DOL) 1 to 19 to either room air (0.21; controls) or to fractions of inspired oxygen (FiO) of 0.6, 0.8, and 1.0. Our primary outcome parameters were histopathologic analyses of heart, lungs, and respiratory system mechanics, assessed via image analysis tools and the forced oscillation technique, respectively.
Exposure to FiO of 0.8 and 1.0 resulted in significantly lower body weights and elevated coefficients of lung tissue damping (G) and elastance (H) when compared with controls. Hysteresivity (η) was lower due to a more pronounced increase of H when compared with G. A positive structure-function relation was demonstrated between H and the lung parenchymal content of α-smooth muscle actin (α-SMA) under hyperoxic conditions. Moreover, histology and morphometric analyses revealed alveolar simplification, fewer pulmonary arterioles, increased α-SMA content in pulmonary vessels, and right heart hypertrophy following hyperoxia. Also, in comparison to controls, hyperoxia resulted in significantly lower plasma levels of vascular endothelial growth factor (VEGF). Lastly, rats in hyperoxia showed hyperactive and a more explorative behaviour.
Our in vivo infant rat model mimics clinical key features of BPD. To the best of our knowledge, this is the first BPD rat model demonstrating an association between lung structure and function. Moreover, we provide additional evidence that infant rats subjected to hyperoxia develop rarefaction of pulmonary vessels, augmented vascular α-SMA, and adaptive cardiac hypertrophy. Thus, our model provides a clinically relevant tool to further investigate diseases related to O toxicity and to evaluate novel pharmacological treatment strategies.
高氧诱导的支气管肺发育不良（BPD）模型对于更好地理解和影响这种慢性疾病的长期肺、心血管和神经后遗症至关重要。只有少数实验研究系统地比较了结构改变与肺功能测量。
在三个独立的连续系列中，Sprague-Dawley 婴儿大鼠从出生第 1 天（DOL）1 至 19 天暴露于室内空气（0.21；对照组）或吸入氧分数（FiO）为 0.6、0.8 和 1.0。我们的主要观察参数是通过图像分析工具和强迫振荡技术分别评估心脏、肺和呼吸系统力学的组织病理学分析。
与对照组相比，FiO 为 0.8 和 1.0 的暴露导致体重显著降低，肺组织阻尼（G）和弹性（H）系数升高。由于 H 相对于 G 的显著增加，滞后（η）降低。在高氧条件下，H 与肺实质α-平滑肌肌动蛋白（α-SMA）含量之间存在正的结构-功能关系。此外，组织学和形态计量学分析显示，高氧后肺泡简化，肺小动脉减少，肺血管α-SMA 含量增加，右心肥厚。与对照组相比，高氧还导致血管内皮生长因子（VEGF）的血浆水平显著降低。最后，高氧组大鼠表现出多动和更具探索性的行为。
我们的体内婴儿大鼠模型模拟了 BPD 的临床关键特征。据我们所知，这是第一个证明 BPD 大鼠模型中肺结构与功能之间存在关联的模型。此外，我们提供了额外的证据，表明接受高氧的婴儿大鼠会出现肺血管稀疏、血管α-SMA 增加和适应性心脏肥大。因此，我们的模型为进一步研究与 O 毒性相关的疾病和评估新的药物治疗策略提供了一个有临床意义的工具。
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