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The effects of neonatal inhalation of hyperoxic gas on airway development and lung function in later life
thesisposted on 06.02.2017, 02:14 by O'Reilly, Megan
Very preterm infants usually require supplemental oxygen therapy to survive. However, high concentrations of oxygen (i.e. inhalation of hyperoxic gas) can contribute to bronchopulmonary dysplasia (BPD). Children, adolescents, and adults who were born very preterm and developed BPD have an increased risk of poor pulmonary function. This suggests that the small conducting airways (bronchioles), which are major determinants of lung function, may be permanently affected. However, little is known about the effects of prolonged early-life exposure to hyperoxic gas on the development of the bronchioles and their later function. Thus, the primary aim was to determine how development and later function of the bronchioles are affected by early exposure to hyperoxic gas. Newborn mice were exposed to hyperoxic gas during the late-saccular to early-alveolar stages of lung development, which is a similar stage of lung development to that of human infants born very preterm. Mice were exposed to hyperoxic gas (65% oxygen) for the first 7 days after birth; thereafter they were raised in room air (21% oxygen) until early (P56d) and mid-late (P10mo) adulthood. Control mice breathed room air for the entire experimental period. Neonatal exposure to hyperoxic gas resulted in significant, persistent alterations to the bronchiolar walls. Immediately following the period of hyperoxia (P7d), there was an increase in epithelial cell proliferation in the bronchioles. At P56d, neonatal hyperoxia resulted in an increased amount of collagen in the bronchiolar wall. By P10mo, neonatal hyperoxia resulted in increased bronchiolar smooth muscle, accompanied by fewer bronchiolar-alveolar attachments. At all three time-points (P7d, P56d, P10mo) the gas-exchanging region of the lung of hyperoxia-exposed mice had enlarged alveoli and less parenchymal tissue. Structural changes in the bronchioles and gas-exchanging region of the lung were not associated with alterations in resting lung function, but were associated with alterations in lung function when challenged with a bronchoconstrictor. At P56d there was a trend for lower transpulmonary resistance and higher dynamic compliance of the respiratory system when challenged with a bronchoconstrictor, and at P10mo there was a significant increase in respiratory compliance. Neonatal hyperoxia significantly increased the number of immune cells (macrophages) in bronchoalveolar lavage fluid in adult mice. Neonatal hyperoxia also restricted postnatal growth, and when this was eliminated, the effects of hyperoxia on the bronchioles in adulthood were altered. In the absence of growth restriction, neonatal hyperoxia resulted in bronchioles with alterations in the proportions of Clara and ciliated cells; bronchiolar wall collagen was also reduced. Conclusion: Inhalation of hyperoxic gas for 7 days during the saccular-alveolar stage of lung development causes persistent alterations in the structure of the bronchioles, in addition to alveolar enlargement, increased numbers of pulmonary immune cells and altered lung function in adulthood. These studies also show that postnatal growth restriction can alter the hyperoxia-induced bronchiolar remodelling. Information gained from these studies highlights the adverse effects of hyperoxia-exposure in early-life on bronchiolar development, especially if combined with growth restriction.