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Published ahead of print on February 21, 2008, doi:10.1164/rccm.200712-1839OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 10, May 2008, 1103-1110

A more recent version of this article appeared on May 15, 2008
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Submitted on December 17, 2007
Accepted on February 21, 2008

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

Michael A O'Reilly1*, Shauna H Marr2, Min Yee3, Sharon A McGrath-Morrow4, and B. Paige Lawrence2

1 Department of Pediatrics, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA; Environmental Medicine, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA, 2 Environmental Medicine, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA, 3 Department of Pediatrics, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA, 4 Department of Pediatric Pulmonary, Johns Hopkins School of Medicine, Baltimore, MD, USA

* To whom correspondence should be addressed. 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 MCP-1 (CCL2) in lavage fluid, while infection-associated changes in IFN-{gamma}, IL-1{beta}, IL-6, TNF-{alpha}, KC, GM-CSF, and MIP-1{alpha}, 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




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