Prolonged Postnatal Hypoxia Impairs Lung Development and Causes Severe Pulmonary Hypertension in Mice.

Abstract

Background: In children born at high altitude, lung development is affected by hypoxia, which can lead to pulmonary hypertension and right ventricular failure. Animal models of postnatal, transient, hypoxia failed to reproduce these conditions seen in children living at high altitude. The aim of this study was to establish a mouse model of pediatric pulmonary hypertension associated with abnormal lung development.

Methods: C57bl/6J mice were exposed to normobaric hypoxia at 11% inspired fraction of oxygen starting on postnatal-days 1 to 4 ("11%-birth"). At age 8 weeks, pulmonary arterial pressure and right ventricular function were assessed using echocardiography and invasive hemodynamics. The physiology and the structure of lung parenchyma and vasculature were assessed through evaluations of gas exchange, respiratory mechanics, and histopathology. Results were compared with control mice breathing 21% inspired fraction of oxygen for 8 weeks (21%-birth), and to adult mice breathing 11% inspired fraction of oxygen for 8 weeks (11%-adult).

Results: Seventy percent of 11%-birth mice survived until age 8 weeks; the mice subsequently experienced a steady decline in survival, with a median lifespan of 150 days. Mice that survived for 8 weeks had evidence of impaired lung development, such as alveolar and vascular simplification with muscularization of small pulmonary vessels, impaired gas exchange, and altered respiratory mechanics. These changes were associated with reduced exercise capacity, severe pulmonary hypertension, and right ventricular failure. Adult mice subjected to chronic hypoxia had mild changes in the pulmonary vasculature resulting in mild pulmonary hypertension without right ventricular dysfunction.

Conclusions: This mouse model of prolonged hypoxia beginning early after birth offers a novel approach to explore treatments for pediatric pulmonary hypertension linked to abnormalities in lung development.