Early exposure to hyperoxia or hypoxia adversely impacts cardiopulmonary development

• Published in: American journal of respiratory cell and molecular biology Vol. 52; no. 5; pp. 594 - 602
• Main Authors: Ramani, Manimaran, Bradley, Wayne E, Dell'Italia, Louis J, Ambalavanan, Namasivayam
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01-05-2015
• Subjects: Actins - metabolism; Age Factors; Animals; Animals, Newborn; Blood Pressure; Bronchial Hyperreactivity - etiology; Bronchial Hyperreactivity - physiopathology; Bronchoconstriction; Cardiovascular System - growth & development; Cardiovascular System - physiopathology; Collagen; Collagen - metabolism; Disease Models, Animal; Elastin - metabolism; Hyperoxia; Hyperoxia - complications; Hyperoxia - metabolism; Hyperoxia - physiopathology; Hypoxia; Hypoxia - complications; Hypoxia - metabolism; Hypoxia - physiopathology; Laboratory animals; Lung - growth & development; Lung - metabolism; Lung - physiopathology; Lung Compliance; Mice, Inbred C57BL; Original Research; Oxidative stress; Pathogenesis; Premature birth; Pulmonary arteries; Pulmonary hypertension; Receptor, Muscarinic M2 - metabolism; Respiratory distress syndrome; Rodents; Smooth muscle; Time Factors; Ventilation; Ventricular Dysfunction, Left - etiology; Ventricular Dysfunction, Left - physiopathology; Ventricular Function, Left; lung function tests; newborn; respiratory function tests; lung development; airway reactivity
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2013-0491OC

Preterm infants are at high risk for long-term abnormalities in cardiopulmonary function. Our objectives were to determine the long-term effects of hypoxia or hyperoxia on cardiopulmonary development and function in an immature animal model. Newborn C57BL/6 mice were exposed to air, hypoxia (12% oxygen), or hyperoxia (85% oxygen) from Postnatal Day 2-14, and then returned to air for 10 weeks (n = 2 litters per condition; > 10/group). Echocardiography, blood pressure, lung function, and lung development were evaluated at 12-14 weeks of age. Lungs from hyperoxia- or hypoxia-exposed mice were larger and more compliant (compliance: air, 0.034 ± 0.001 ml/cm H2O; hypoxia, 0.049 ± 0.002 ml/cm H2O; hyperoxia, 0.053 ± 0.002 ml/cm H2O; P < 0.001 air versus others). Increased airway reactivity, reduced bronchial M2 receptor staining, and increased bronchial α-smooth muscle actin content were noted in hyperoxia-exposed mice (maximal total lung resistance with methacholine: air, 1.89 ± 0.17 cm H2O ⋅ s/ml; hypoxia, 1.52 ± 0.34 cm H2O ⋅ s/ml; hyperoxia, 4.19 ± 0.77 cm H2O ⋅ s/ml; P < 0.004 air versus hyperoxia). Hyperoxia- or hypoxia-exposed mice had larger and fewer alveoli (mean linear intercept: air, 40.2 ± 0. 0.8 μm; hypoxia, 76.4 ± 2.4 μm; hyperoxia, 95.6 ± 4.6 μm; P < 0.001 air versus others; radial alveolar count [n]: air, 11.1 ± 0.4; hypoxia, 5.7 ± 0.3; hyperoxia, 5.6 ± 0.3; P < 0.001 air versus others). Hyperoxia-exposed adult mice had left ventricular dysfunction without systemic hypertension. In conclusion, exposure of newborn mice to hyperoxia or hypoxia leads to cardiopulmonary abnormalities in adult life, similar to that described in ex-preterm infants. This animal model may help to identify underlying mechanisms and to develop therapeutic strategies for pulmonary morbidity in former preterm infants.