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.

Can maternal DHA supplementation offer long-term protection against neonatal hyperoxic lung injury?

“…These could predispose the neonates with BPD to the development of respiratory illnesses later in their life. Similar persistent findings into adulthood have been found in neonatal mice exposed to hyperoxia (4,5,34,38,48).…”

“…These could predispose the neonates with BPD to the development of respiratory illnesses later in their life. Similar persistent findings into adulthood have been found in neonatal mice exposed to hyperoxia (4,5,34,38,48).Several investigators have noted the protective effects of DHA and its downstream metabolites in various lung diseases. Levels of DHA decrease in premature neonates after birth (24), and this could potentially exacerbate the adverse effects of infection, inflammation, or oxidative stress.…”

Endothelial Monocyte-Activating Polypeptide II Mediates Macrophage Migration in the Development of Hyperoxia-Induced Lung Disease of Prematurity

“…Some studies suggested that hyperoxia increased compliance as in the case of emphysematous lungs, whereas other studies concluded hyperoxia decreased compliance because the lungs are less pliable (47)(48)(49)(50). We tested murine pulmonary outcomes at 6 weeks in accordance with previous studies (36,47,49).…”

“…In BPD, hyperoxia-induced inflammation has also been linked to impaired lung biophysical properties, but with conflicting results; both increasing and decreasing compliance have been described (47)(48)(49). Some studies suggested that hyperoxia increased compliance as in the case of emphysematous lungs, whereas other studies concluded hyperoxia decreased compliance because the lungs are less pliable (47)(48)(49)(50).…”

Oxygen Use in Neonatal Care: A Two-edged Sword

“…Oxygen exposure in the neonatal period has been demonstrated to affect lungs of mice by increasing airway reactivity and persistent inflammation with alteration in the innate immunoregulatory pathways that contribute to “poorer resistance” to respiratory viral infections in adulthood (61, 62). Furthermore, the exposure of newborn mice to hyperoxia may lead to long-term cardiac abnormalities, such as left ventricular dysfunctions (63), and neurodevelopmental impairments in adult life, as demonstrated by abnormal behavior, deficits in spatial and recognition memory, small hippocampal dimensions, in the absence of intracranial pathology such as intraventricular hemorrhage or periventricular leukomalacia in the neonatal period (64). …”