Morphological characterization of pulmonary microvascular disease in bronchopulmonary dysplasia caused by hyperoxia in newborn mice
Pulmonary microvascular injury is associated with the pathogenesis of bronchopulmonary dysplasia (BPD). To characterize the mechanisms of pulmonary vascular disease resulting from BPD, we studied the ultrastructural changes affecting pulmonary microvasculature.
Newborn ICR mice were exposed to 85% hyperoxia or normoxia for 14 days, and then normal air replacement conditions for the following 7 days. At postnatal day (P)14 and P21, lungs were harvested for ultrastructural examination and assessment of pulmonary hypertension.
The ultrastructure of pulmonary microvasculature in the hyperoxia-exposed lungs revealed a collapsed capillary lumen. This was due to the abnormal morphology of endothelial cells (ECs) characterized by heterogeneously thick cytoplasm. Compared to normal air controls, the specimens displayed also remarkably thick blood–air barriers (BABs), most of which were occupied by EC layer components. Structural changes were accompanied by increased pulmonary artery medial thickness and right ventricular hypertrophy (RVH). Moreover, abnormalities in ECs persisted even after exposure to 7 days of normal air replacement conditions. Results were confirmed by morphometric quantification.
Our results suggest that the abnormal morphology of capillary ECs and thick BABs correlates with pulmonary artery remodeling and RVH. These ultrastructural changes might represent possible mechanisms of secondary pulmonary hypertension in BPD.
KeywordsBronchopulmonary dysplasia Hyperoxia Newborn Pulmonary hypertension Pulmonary microvascular disease
This study was supported by the Medical Research Institute, Tokyo Women’s Medical University. We would like to thank T. Matsuda, Tohoku University, K. Chou, Hokkaido University, and S. Shimizu, Tokyo Women’s Medical University, for their excellent support during lung structural analysis in this study. We would like to thank Editage (http://www.editage.jp) for English language editing.
This study was supported by a Takako Satake Research Fellowship Grant (Grant Number 54) and the Ministry of Education, Culture, Sports, Science and Technology (MEXT) KAKENHI (Grant Number 16K10111).
Compliance with ethical standards
Conflict of interest
Teijin Pharma Ltd., Tokyo, Japan kindly provided the home oxygen condenser (TO-90-7H) without any compensation. They had no control over the interpretation, writing, or publication of this study. The authors have no financial relationships relevant to this article to disclose.
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