An Experimental Model of Bronchopulmonary Dysplasia Features Long-Term Retinal and Pulmonary Defects but Not Sustained Lung Inflammation

Abstract

Bronchopulmonary dysplasia (BPD) is a severe lung disease that affects preterm infants receiving oxygen therapy. No standardized, clinically-relevant BPD model exists, hampering efforts to understand and treat this disease. This study aimed to evaluate and confirm a candidate model of acute and chronic BPD, based on exposure of neonatal mice to a high oxygen environment during key lung developmental stages affected in preterm infants with BPD. Neonatal C57BL/6 mouse pups were exposed to 75% oxygen from postnatal day (PN)-1 for 5, 8, or 14 days, and their lungs were examined at PN14 and PN40. While all mice showed some degree of lung damage, mice exposed to hyperoxia for 8 or 14 days exhibited the greatest septal wall thickening and airspace enlargement. Furthermore, when assessed at PN40, mice exposed for 8 or 14 days to supplemental oxygen exhibited augmented septal wall thickness and emphysema, with the severity increased with the longer exposure, which translated into a decline in respiratory function at PN80 in the 14-day model. In addition to this, mice exposed to hyperoxia for 8 days showed significant expansion of alveolar epithelial type II cells as well as the greatest fibrosis when assessed at PN40 suggesting a healing response, which was not seen in mice exposed to high oxygen for a longer period. While evidence of lung inflammation was apparent at PN14, chronic inflammation was absent from all three models. Finally, exposure to high oxygen for 14 days also induced concurrent outer retinal degeneration. This study shows that early postnatal exposure to high oxygen generates hallmark acute and chronic pathologies in mice that highlights its use as a translational model of BPD.

Landscape analysis for a neonatal disease progression model of bronchopulmonary dysplasia: Leveraging clinical trial experience and real-world data

“…Despite the number of animal models, no clinically relevant and standardized model exists, leaving several gaps that must be addressed to optimize the pathophysiology and treatment of BPD ( Wickramasinghe et al, 2021a ). The vast majority of preclinical models of BPD aim to achieve a simplified alveolar structure with disordered surrounding vasculature in order to study relevant mechanisms of malformation.…”

“…A consequence of focusing on disease onset is that these preclinical models have yet to expand into longitudinal frameworks that connect to long-term outcomes. Few studies continue experimental observation beyond the well-controlled period of pathogenic insults due to the extreme financial and time commitments ( Yoder and Coalson, 2014 ; Wickramasinghe et al, 2021a ). The introduction of an intermittent insult methodology that combines injury and repair phases to align with clinical protocols more closely has expanded some study durations, but not enough to capture long-term sequelae of the disease ( Ratner et al, 2009 ).…”

“…Establishing standardized protocols could facilitate a more systematic review of the direct impact that various insults have on lung development. While many studies report structural and histological findings that demonstrate alveolar simplification, few are accompanied by physiological metrics of gas exchange ( Reynolds et al, 2010 ; Wickramasinghe et al, 2021a ). Including any functional metrics would add a quantitative layer to these studies and help elucidate structure-function relationships throughout lung development, which would be useful from a longitudinal mathematical modeling standpoint.…”