title: Early exposure to hyperoxia or hypoxia adversely impacts cardiopulmonary development.
abstract: 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.
authors.affiliation: Departments of 1 Pediatrics.
authors.forename: Manimaran
authors.initials: M
authors.lastname: Ramani
authors.forename: Wayne E
authors.initials: WE
authors.lastname: Bradley
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'Italia
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
mesh_terms: D000199:Actins / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000503:physiopathology; D016084:Bronchoconstriction; D002319:Cardiovascular System / Q000254:growth & development / Q000503:physiopathology*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D018496:Hyperoxia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D008168:Lung / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology*; D008170:Lung Compliance; D008810:Mice, Inbred C57BL; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology; D016277:Ventricular Function, Left
chemical_list: D000199:Actins; D043585:Receptor, Muscarinic M2; C544013:alpha-smooth muscle actin, mouse; D003094:Collagen; D004549:Elastin
keywords: airway reactivity; lung development; lung function tests; newborn; respiratory function tests