title: Neonatal hyperoxia alters the host response to influenza A virus infection in adult mice through multiple pathways.
abstract: Exposing preterm infants or newborn mice to high concentrations of oxygen disrupts lung development and alters the response to respiratory viral infections later in life. Superoxide dismutase (SOD) has been separately shown to mitigate hyperoxia-mediated changes in lung development and attenuate virus-mediated lung inflammation. However, its potential to protect adult mice exposed to hyperoxia as neonates against viral infection is not known. Here, transgenic mice overexpressing extracellular (EC)-SOD in alveolar type II epithelial cells are used to test whether SOD can alleviate the deviant pulmonary response to influenza virus infection in adult mice exposed to hyperoxia as neonates. Fibrotic lung disease, observed following infection in wild-type (WT) mice exposed to hyperoxia as neonates, was prevented by overexpression of EC-SOD. However, leukocyte recruitment remained excessive, and levels of monocyte chemoattractant protein (MCP)-1 remained modestly elevated following infection in EC-SOD Tg mice exposed to hyperoxia as neonates. Because MCP-1 is often associated with pulmonary inflammation and fibrosis, the host response to infection was concurrently evaluated in adult Mcp-1 WT and Mcp-1 knockout mice exposed to neonatal hyperoxia. In contrast to EC-SOD, excessive leukocyte recruitment, but not lung fibrosis, was dependent upon MCP-1. Our findings demonstrate that neonatal hyperoxia alters the inflammatory and fibrotic responses to influenza A virus infection through different pathways. Therefore, these data suggest that multiple therapeutic strategies may be needed to provide complete protection against diseases attributed to prematurity and early life exposure to oxygen.
authors.affiliation: Dept. of Pediatrics, Box 850, The Univ. of Rochester, School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642. michael_oreilly@urmc.rochester.edu.
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Buczynski
authors.forename: Min
authors.initials: M
authors.lastname: Yee
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Martin
authors.forename: B Paige
authors.initials: BP
authors.lastname: Lawrence
authors.forename: Michael A
authors.initials: MA
authors.lastname: O'Reilly
mesh_terms: D000375:Aging / Q000276:immunology / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D018932:Chemokine CCL2 / Q000378:metabolism; D018450:Disease Progression; D005110:Extracellular Space / Q000201:enzymology; D005260:Female; D054884:Host-Pathogen Interactions / Q000276:immunology*; D018496:Hyperoxia / Q000150:complications* / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D009980:Influenza A virus / Q000502:physiology*; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009976:Orthomyxoviridae Infections / Q000150:complications* / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D016019:Survival Analysis
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D013482:Superoxide Dismutase
keywords: lung fibrosis; monocyte chemoattractant protein-1; respiratory viral infection; superoxide dismutase