During hyperoxia, high oxygen levels in the mitochondria lead to an increase in generation of reactive oxygen species (ROS), including superoxide.²

Preclinical models demonstrate reactivity between ROS and biomolecules, where ROS are capable of damaging DNA, proteins, carbohydrates, and lipids. These reactions can cause free radical–mediated alterations that can lead to oxidative stress and numerous pathophysiologic disorders.^2-5

Lung tissue cells are exposed to the highest concentrations of oxygen in the body and are at the greatest risk for hyperoxia, leading to depleted energy reserves, altered cell-signaling cascades, oxidative reactions, and cell death or tissue damage.^2,6

Studies using preclinical models of neonates have demonstrated that the production of ROS disrupts the balance between oxidants and antioxidants in the lungs, leading to oxidative stress and the induction of oxidative stress–signaling pathways.^2,7,8

In addition, preclinical data show that oxidative stress can result in long-term neonatal lung injury, tissue damage, and neurologic diseases.^2,3

Defense mechanisms against ROS are critical to the prevention or attenuation of oxidant-mediated lung tissue damage.⁹

Superoxide dismutase (SOD) is one of the key enzymes that protects against oxidant-related damage by promoting the elimination of superoxide radicals. In order to protect the lung tissue against hyperoxic conditions, there must be a sufficient amount of active SOD to eliminate the radicals produced.⁹

In premature neonates, SOD activity is relatively low compared with full-term neonates. Even term neonates have lower levels of SOD activity relative to adults. This may contribute to the neonates’ increased susceptibility to oxidant injury.^9,10

Studies have suggested a link between oxygen supplementation and bronchopulmonary dysplasia (BPD) in premature infants. BPD is suggested to be one of the major causes of morbidity in premature infants and is characterized by arrested lung growth and inhibited alveolar development.^9,11

BPD was first described in 1967 by Northway et al. The paper noted severe respiratory distress syndrome in 32 neonates born after 32 weeks gestation who were treated with prolonged mechanical ventilation at high concentrations of oxygen.¹²

BPD appears to be multifactorial and the various factors act in a cumulative way. Oxygen exposure is one of those factors.¹³

Oxygen exposure and the generation of free radicals is suggested to be one of the major causes of lung damage in BPD.^14,15 Oxygen exposure also appears to play a role in the upregulation of proinflammatory cytokines. In a study of infants on mechanical ventilation, NF-κB concentrations in tracheobronchial lavage significantly correlated to oxygen exposure during the first 3 days of life with much higher concentrations in those who either died or had BPD. NF-κB is a ubiquitous transcription factor that promotes the expression of many genes, including proinflammatory cytokines associated with the development of BPD.¹⁶ The clinical relevance of this has not been fully established.