Long-term pulmonary and cardiovascular morbidities of neonatal hyperoxia exposure in mice

Abstract

Pulmonary hypertension (PH) frequently occurs in infants with bronchopulmonary dysplasia (BPD), causing increased mortality and right ventricular (RV) dysfunction that persists into adulthood. A first step in developing better therapeutic options is identifying and characterizing an appropriate animal model. Previously, we characterized the short-term morbidities of a model in which C57BL/6J wild-type (WT) mice were exposed to 70% O (hyperoxia) during the neonatal period. Here, we aimed to determine the long-term morbidities using lung morphometry, echocardiography (Echo), and cardiac magnetic resonance imaging (cMRI). The major highlight of this study is the use of the state-of-the art imaging technique, cMRI, in mice to characterize the long-term cardiac effects of neonatal hyperoxia exposure. To this end, WT mice were exposed to 21% O (normoxia) or hyperoxia for two weeks of life, followed by recovery in normoxia for six weeks. Alveolarization, pulmonary vascularization, pulmonary hypertension, and RV function were quantified at eight weeks. We found that hyperoxia exposure resulted in persistent alveolar and pulmonary vascular simplification. Furthermore, the Echo and cMRI studies demonstrated that hyperoxia-exposed mice had signs of PH and RV dysfunction as indicated by increased RV pressure, mass, and end-systolic and -diastolic volumes, and decreased RV stroke volume and ejection fractions. Taken together, our results demonstrate that neonatal hyperoxia exposure in mice cause cardiopulmonary morbidities that persists into adulthood and provides evidence for the use of this model to develop novel therapies for BPD infants with PH.

Tie-2 Cre-Mediated Deficiency of Extracellular Signal-Regulated Kinase 2 Potentiates Experimental Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension in Neonatal Mice

“…Hyperoxia impairs signaling pathways necessary for lung development and repair [43,44], disrupts alveolarization and pulmonary vascularization in preterm infants [45] and newborn mice [46], and causes BPD. Furthermore, our hyperoxia model is shown to recapitulate the short-and long-term phenotype of BPD infants with PH [33,34]. Consistent with this notion, our hyperoxia-exposed animals displayed alveolar and pulmonary vascular simplification.…”

Hyperoxia and Lungs: What We Have Learned From Animal Models

“…Pulmonary hypertension signs such as arterial thickness and right ventricle hypertrophy were observed in mice with postnatal hyperoxia, among other systemic vascular structural effects (126)(127)(128).…”

Echocardiographic assessment of right ventricular function in experimental pulmonary hypertension

“…12,13 Pulmonary acceleration time (PAT) and ratio of PAT/pulmonary ejection time (PET) are also two good parameters that reflect the afterload of RV. 15 Echocardiography, a non-invasive and cost-effective approach, is now commonly used in the clinical 15–18 and preclinical 19–23 realm for real-time measurement of such parameters in patients and experimental models of PH.…”