Neonatal hyperoxia leads to persistent alterations in NK responses to influenza A virus infection

Am J Physiol Lung Cell Mol Physiol. 2015 Jan 1;308(1):L76-85. doi: 10.1152/ajplung.00233.2014. Epub 2014 Nov 7.


Respiratory distress in preterm or low birth weight infants is often treated with supplemental oxygen. However, this therapy can disrupt normal lung development and architecture and alter responses to respiratory insults. Similarly, exposure of newborn mice to 100% oxygen during saccular lung development leads to permanent alveolar simplification, and upon challenge with influenza A virus, mice exhibit reduced host resistance. Natural killer (NK) cells are key players in antiviral immunity, and emerging evidence suggest they also help to maintain homeostasis in peripheral tissues, including the lung, by promoting epithelial cell regeneration via IL-22. We tested the hypothesis that adult mice exposed to hyperoxia as neonates have modified NK cell responses to infection. We report here that mice exposed to neonatal hyperoxia had fewer IL-22(+) NK cells in their lungs after influenza virus challenge and a parallel increase in IFN-γ(+) NK cells. Using reciprocal bone marrow chimeric mice, we show that exposure of either hematopoietic or nonhematopoietic cells was sufficient to increase the severity of infection and to diminish the frequency of IL-22(+) NK cells in the infected lung. Overall, our findings suggest that neonatal hyperoxia leads to long-term changes in the reparative vs. cytotoxic nature of NK cells and that this is due in part to intrinsic changes in hematopoietic cells. These differences may contribute to how oxygen alters the host response to respiratory viral infections.

Keywords: hematopoietic; innate immunity; respiratory infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Hyperoxia / immunology*
  • Hyperoxia / pathology
  • Immunity, Cellular*
  • Influenza A virus / immunology*
  • Interferon-gamma / immunology
  • Interleukins / immunology
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / pathology
  • Mice
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / pathology
  • Pulmonary Alveoli / immunology*
  • Pulmonary Alveoli / pathology


  • Interleukins
  • Interferon-gamma
  • interleukin-22