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Neonatal Hyperoxia Enhances the Inflammatory Response in Adult Mice Infected with Influenza A Virus

¹ Department of Pediatrics and ² Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, New York; and ³ Department of Pediatric Pulmonary, Johns Hopkins School of Medicine, Baltimore Maryland

Correspondence and requests for reprints should be addressed to Michael A. O'Reilly, Ph.D., Department of Pediatrics, Box 850, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642. E-mail: michael_oreilly{at}urmc.rochester.edu

Rationale: Lungs of adult mice exposed to hyperoxia as newborns are simplified and exhibit reduced function much like that observed in people who had bronchopulmonary dysplasia (BPD) as infants. Because survivors of BPD also show increased risk for symptomatic respiratory infections, we investigated how neonatal hyperoxia affected the response of adult mice infected with influenza A virus infection.

Objectives: To determine whether neonatal hyperoxia increased the severity of influenza A virus infection in adult mice.

Methods: Adult female mice exposed to room air or hyperoxia between Postnatal Days 1 and 4 were infected with a sublethal dose of influenza A virus.

Measurements and Main Results: The number of macrophages, neutrophils, and lymphocytes observed in airways of infected mice that had been exposed to hyperoxia as neonates was significantly greater than in infected siblings that had been exposed to room air. Enhanced inflammation correlated with increased levels of monocyte chemotactic protein-1 (CCL2) in lavage fluid, whereas infection-associated changes in IFN-, IL-1β, IL-6, tumor necrosis factor-, KC, granulocyte-macrophage colony–stimulating factor, and macrophage inflammatory protein-1, and production of virus-specific antibodies, were largely unaffected. Increased mortality of mice exposed to neonatal hyperoxia occurred by Day 14 of infection, and was associated with persistent inflammation and fibrosis.

Conclusions: These data suggest that the disruptive effect of hyperoxia on neonatal lung development also reprograms key innate immunoregulatory pathways in the lung, which may contribute to exacerbated pathology and poorer resistance to respiratory viral infections typically seen in people who had BPD.

Key Words: bronchopulmonary dysplasia • hyperoxia • infection • lung inflammation • virus

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Despite improved therapies for treating bronchopulmonary dysplasia (BPD), it is unknown why survivors are at increased risk for symptomatic respiratory infections and are often rehospitalized. What This Study Adds to the Field This study shows that neonatal hyperoxia exacerbates the inflammatory response in adult mice infected with influenza A virus, implying that key innate immunoregulatory pathways may be disrupted in people who had BPD.