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

Int J Chron Obstruct Pulmon Dis. 2016 Jul 14;11:1597-605. doi: 10.2147/COPD.S109510. eCollection 2016.

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.

Keywords: hyperoxia; inducible nitric oxide synthase; inflammation; malondialdehyde adducts; oxidative stress.

MeSH terms

  • Actins / metabolism
  • Animals
  • Animals, Newborn
  • Bronchopulmonary Dysplasia / diagnosis
  • Bronchopulmonary Dysplasia / etiology*
  • Bronchopulmonary Dysplasia / physiopathology
  • Disease Models, Animal
  • Disease Progression
  • Echocardiography, Doppler, Pulsed*
  • Feasibility Studies
  • Female
  • Hemodynamics
  • Hyperoxia / complications*
  • Hyperoxia / metabolism
  • Hyperoxia / physiopathology
  • Hypertension, Pulmonary / diagnostic imaging*
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / metabolism
  • Hypertension, Pulmonary / physiopathology
  • Lung / blood supply*
  • Lung / metabolism
  • Lung / physiopathology
  • Male
  • Malondialdehyde / metabolism
  • Mice, Inbred C57BL
  • Nitric Oxide Synthase Type II / metabolism
  • Oxidative Stress
  • Predictive Value of Tests
  • Pulmonary Artery / diagnostic imaging*
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / physiopathology
  • Pulmonary Disease, Chronic Obstructive / diagnosis
  • Pulmonary Disease, Chronic Obstructive / etiology
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Pulmonary Disease, Chronic Obstructive / prevention & control*
  • Time Factors
  • Vascular Remodeling
  • von Willebrand Factor / metabolism

Substances

  • Acta2 protein, mouse
  • Actins
  • von Willebrand Factor
  • Malondialdehyde
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse