It is well known that supplemental
oxygen used to treat preterm infants in respiratory distress is associated with permanently disrupting lung development and the host response to influenza A virus (IAV). However, many infants who go home with normally functioning lungs are also at risk for hyperreactivity after a respiratory
viral infection. We recently reported a new, low-dose
hyperoxia mouse model (40% for 8 days; 40×8) that causes a transient change in lung function that resolves, rendering 40×8 adult animals functionally indistinguishable from room air controls. Here we report that when infected with IAV, 40×8 mice display an early transient activation of TGFβ signaling and later airway hyperreactivity associated with peribronchial
inflammation (profibrotic macrophages) and
fibrosis compared with infected room air controls, suggesting neonatal
oxygen induced hidden molecular changes that prime the lung for hyperreactive airways disease. Although searching for potential activators of TGFβ signaling, we discovered that thrombospondin-1 (TSP-1) is elevated in naïve 40×8 mice compared with controls and localized to lung megakaryocytes and platelets before and during IAV
infection. Elevated
TSP-1 was also identified in human autopsy samples of former preterm infants with
bronchopulmonary dysplasia. These findings reveal how low doses of
oxygen that do not durably change lung function may prime it for hyperreactive airways disease by changing expression of genes, such as
TSP-1, thus helping to explain why former preterm infants who have normal lung function are susceptible to
airway obstruction and increased morbidity after
viral infection.