Phenotypic assessment of pulmonary hypertension using high-resolution echocardiography is feasible in neonatal mice with experimental bronchopulmonary dysplasia and pulmonary hypertension: a step toward preventing chronic obstructive pulmonary disease

Abstract

Bronchopulmonary dysplasia (BPD) and chronic obstructive pulmonary disease (COPD) are chronic lung diseases of human infants and adults, respectively, that are characterized by alveolar simplification. One-third of the infants with severe BPD develop pulmonary hypertension (PH). More importantly, PH increases morbidity and mortality in BPD patients. Additionally, COPD is a common respiratory morbidity in former BPD patients. The lack of an appropriate small animal model wherein echocardiography (Echo) can demonstrate PH is one of the major barriers to understand the molecular mechanisms of the disease and, thereby, develop rational therapies to prevent and/or treat PH in BPD patients. Thus, the goal of this study was to establish a model of experimental BPD and PH and investigate the feasibility of Echo to diagnose PH in neonatal mice. Since hyperoxia-induced oxidative stress and inflammation contributes to the development of BPD with PH, we tested the hypothesis that exposure of newborn C57BL/6J mice to 70% O2 (hyperoxia) for 14 days leads to lung oxidative stress, inflammation, alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and Echo evidence of PH. Hyperoxia exposure caused lung oxidative stress and inflammation as evident by increased malondialdehyde adducts and inducible nitric oxide synthase, respectively. Additionally, hyperoxia exposure caused growth restriction, alveolar and pulmonary vascular simplification, and pulmonary vascular remodeling. At 14 days of age, Echo of these mice demonstrated that hyperoxia exposure decreased pulmonary acceleration time (PAT) and PAT/ejection time ratio and increased right ventricular free wall thickness, which are indicators of significant PH. Thus, we have demonstrated the feasibility of Echo to phenotype PH in neonatal mice with experimental BPD with PH, which can aid in discovery of therapies to prevent and/or treat BPD with PH and its sequelae such as COPD in humans.

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 exposure disrupts adrenomedullin signaling in newborn mice: Implications for lung development in premature infants

“…In alignment with other studies [5, 6], we recently demonstrated that hyperoxia-induced lung parenchymal and vascular injury in newborn mice leads to a phenotype that is similar to human BPD [7]. So, we used this model to investigate whether AM signaling is disrupted in experimental BPD.…”

“…We demonstrated that our mouse model of hyperoxia-induced lung injury meets the requirements needed to model BPD with pulmonary hypertension (PH) experimentally [7]. In that study, we observed that hyperoxia exposure disrupted lung development in mice at PND 14.…”

“…Within 24 h of birth, male and female pups were exposed to normoxia (21% O 2 , n=36) or hyperoxia (70% O 2 , n=36) for up to 14 d. The dams were rotated between normoxia- and hyperoxia-exposed litters every 48 h to prevent oxygen toxicity in the dams [7]. Following hyperoxia exposure, mice were allowed to recover in air for 14 d as described previously [20].…”

“…Alveolar development on selected mice was evaluated by radial alveolar counts (RAC) and mean linear intercepts (MLI) [7]. Pulmonary vessel density was determined based on immunohistochemical staining for von Willebrand factor (vWF), which is an endothelial specific marker.…”