Low-dose hyperoxia primes airways for fibrosis in mice after influenza A infection

Am J Physiol Lung Cell Mol Physiol. 2021 Oct 1;321(4):L750-L763. doi: 10.1152/ajplung.00289.2020. Epub 2021 Jul 29.


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.

Keywords: airway hyperreactivity; bronchopulmonary dysplasia; influenza A; neonatal hyperoxia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bronchial Hyperreactivity / pathology*
  • Bronchopulmonary Dysplasia / pathology*
  • Cell Line
  • Disease Models, Animal
  • Dogs
  • Female
  • Humans
  • Hyperoxia / pathology*
  • Influenza A virus / immunology
  • Influenza, Human / pathology
  • Madin Darby Canine Kidney Cells
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Orthomyxoviridae Infections / pathology*
  • Pulmonary Fibrosis / pathology*
  • Pulmonary Fibrosis / virology
  • Thrombospondin 1 / metabolism*
  • Transforming Growth Factor beta / metabolism


  • Thrombospondin 1
  • Transforming Growth Factor beta

Associated data

  • figshare/10.6084/m9.figshare.14051579