Exposing the developing lung to hyperoxic gas: effects on lung development and markers of oxidative stress and inflammation later in life
2017-02-27T05:33:12Z (GMT) by
Owing to lung immaturity, infants born preterm are often administered high levels of oxygen (hyperoxia). However, prolonged hyperoxia can cause oxidative stress and inflammation and can alter lung development, which may contribute to later lung disease. Previous experimental studies of neonatal hyperoxia have largely used oxygen concentrations greater than 80%. There is a need to study the long-term effects of milder oxygen concentrations, which reflect current clinical practice. Preterm infants are likely to have an immature antioxidant system at birth, but how this immaturity contributes to hyperoxia-induced lung injury is poorly understood. As exposure to hyperoxia induces oxidative stress, it is possible that dietary antioxidant supplementation can prevent or reduce the degree of injury. The aim of studies reported in Chapter 3 was to compare the short-term and long-term effects of exposing neonatal mice to either mild (40% O₂) or moderate (65% O₂) hyperoxia for seven days after birth. Controls breathed room air (21% O₂). Lungs were collected at either postnatal day seven (P7d) or adulthood (P56d), after seven weeks of breathing 21% O₂. Unlike neonatal exposure to 65% O₂, exposure to 40% O₂ did not alter lung structure at either age. However, exposure to both 40% and 65% O₂ led to increases in markers of oxidative stress and the number of immune cells in the lung that persisted into adulthood. The aim of studies described in Chapter 4 was to determine the effect of neonatal hyperoxia in mice lacking the gene for glutathione peroxidase 1 (Gpx1; an endogenous antioxidant enzyme), thereby mimicking an immature antioxidant system. Gpx1 knockout and wild-type mice were exposed to 21% or 40% O₂ for seven days after birth. In the absence of Gpx1 expression, neonatal hyperoxia did not increase oxidative stress or alter lung structure; however, the proportion of lymphocytes in the adult lung was increased. Potential redundancy was observed within the model, with the relative gene expression of Gpx2, Gpx3, Gpx4 and Catalase increased at P56d in the Gpx1 knockout mice exposed to 40% O₂. The aim of studies reported in Chapter 5 was to determine whether dietary antioxidants (tomato juice) could protect the lung from the effects of neonatal exposure to 65% O2. Tomato juice supplementation increased lung antioxidant capacity and reduced markers of oxidative stress and inflammation at P7d, but did not prevent decreased alveolarisation following exposure to 65% O₂. At P56d, the supplementation ameliorated the hyperoxia-induced increase in bronchiolar smooth muscle, but did not alter the increase in immune cells in the lung lumen. Conclusions: This thesis shows for the first time that a mild level of neonatal hyperoxia (40% O₂) can cause persistent increases in oxidative stress and immune cell numbers in the lung, in the absence of structural alterations; thus, mild hyperoxia, thought to be clinically benign, can adversely affect the lung in such a way as to increase the risk of later lung disease. The absence of Gpx1 gene expression does not exacerbate hyperoxia-induced alterations in lung structure or increases in oxidative stress, but does alter immune cells in the lung. Finally, dietary antioxidant supplementation may be beneficial in preventing some of the short-term and long-term alterations in the lung induced by neonatal hyperoxia.