Affect of Early Life Oxygen Exposure on Proper Lung Development and Response to Respiratory Viral Infections

Abstract

Children born preterm often exhibit reduced lung function and increased severity of response to respiratory viruses, suggesting that premature birth has compromised proper development of the respiratory epithelium and innate immune defenses. Increasing evidence suggests that premature birth promotes aberrant lung development likely due to the neonatal oxygen transition occurring before pulmonary development has matured. Given that preterm infants are born at a point of time where their immune system is also still developing, early life oxygen exposure may also be disrupting proper development of innate immunity. Here, we review current literature in hopes of stimulating research that enhances understanding of how the oxygen environment at birth influences lung development and host defense. This knowledge may help identify those children at risk for disease and ideally culminate in the development of novel therapies that improve their health.

Keywords: hyperoxia; influenza A virus; innate immunity; lung development; prematurity.

Figure 1

Stages of lung development in the human and mouse. During development, the human (mouse) lung undergoes five successive stages of development; The Embryonic stage 3–6 weeks (e9.5–11.5), the Pseudoglandular stage 6–16 weeks (e11.5–16.5), the Canalicular stage 12–26 weeks (e16.5–17.5), the Saccular stage 24–38 weeks (e17.5–PND4), and the Alveolar stage 38 weeks–2+ years (PND4–28). Preterm children who survive are often born between 24 and 38 weeks of age and are in the saccular stage of development (circled) corresponding to the saccular stage in the mouse from e17.5–PND4.

Figure 2

The early life oxygen environment affects changes in genetic as well as innate immune mechanisms. Cartoon depicting the affect early life oxygen environment imparts on genes that specify lung structure and function with cells involved in innate immunity.

Figure 3

Mice exposed to hyperoxia at birth develop fibrosis after influenza A infection. Adult (8-week old) C57Bl/6J mice exposed to room air (21% oxygen) or hyperoxia (100% oxygen) between postnatal days 0–4 were infected with 120 HAU of influenza A virus (H3N2). Trichrome staining revealed extensive collagen deposition and inflammation in infected mice exposed to neonatal hyperoxia 14 days post infection. This pathology was not evidence in infected siblings exposed to room air at birth.

Figure 4

The oxygen environment at birth affects the severity of respiratory viral infection later in life. Hypothetical graph depicting how exposure to low or high inspired oxygen at birth can increase respiratory morbidity following a respiratory viral infection.