4.7 Article

Hyperoxia-induced lung structure-function relation, vessel rarefaction, and cardiac hypertrophy in an infant rat model

期刊

JOURNAL OF TRANSLATIONAL MEDICINE
卷 17, 期 -, 页码 -

出版社

BMC
DOI: 10.1186/s12967-019-1843-1

关键词

Hyperoxia; Bronchopulmonary dysplasia; Animal model; Respiratory system mechanics; Forced oscillation technique; Hysteresivity eta (eta); alpha-Smooth muscle actin (alpha-SMA); Vascular endothelial growth factor (VEGF); Digital pathology

资金

  1. Zurich Center for Integrative Human Physiology (ZIHP)
  2. Heartbay Foundation (Vaduz)

向作者/读者索取更多资源

Background: 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. Methods: 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(2)) 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. Results: Exposure to FiO(2) 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 (eta) 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 alpha-smooth muscle actin (alpha-SMA) under hyperoxic conditions. Moreover, histology and morphometric analyses revealed alveolar simplification, fewer pulmonary arterioles, increased alpha-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. Conclusions: 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 alpha-SMA, and adaptive cardiac hypertrophy. Thus, our model provides a clinically relevant tool to further investigate diseases related to O-2 toxicity and to evaluate novel pharmacological treatment strategies.

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