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

Abstract

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 infectionassociated changes in IFN-g, IL-1b, IL-6, tumor necrosis factor-a, KC, granulocyte-macrophage colony-stimulating factor, and macrophage inflammatory protein-1a, 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.

Neonatal Hyperoxia Causes Pulmonary Vascular Disease and Shortens Life Span in Aging Mice

“…And like children born prematurely who are often rehospitalized when infected with respiratory syncytial virus, 20,21 adult mice exposed to neonatal hyperoxia show increased susceptibility to influenza A virus infection. 33 Since lung function in late adolescents born prematurely might be deteriorating faster than expected, 24 we decided to investigate whether deficits in lung function and structure changed as oxygen-exposed mice aged. We found elevated lung compliance and reduced tissue elastance activity in aged mice, similar to the changes observed at 8 weeks following exposure to neonatal hyperoxia.…”

“…Not only did neonatal hyperoxia suppress mRNA levels of BMPR1b and Alk-1, it also suppressed expression of BMPR-II and BMPR1a ( Figure 6C). Because pathological signs of PAH were not observed in young adult (8-week-old) mice, 27,33 we also investigated whether BMP signaling was suppressed at this age. Consistent with the lack of overt vascular pathology and mortality at this time, phospho-Smad1/5/8 and expression of BMP receptors were similar between the two groups of mice ( Figure 6, D-F).…”

“…On the other hand, these mice were highly susceptible to influenza A virus infection, with greater inflammation, fibrosis, and mortality compared to siblings exposed to room air. 33 Since children born prematurely also show changes in lung function and increased susceptibility to viral infections, this mouse model may provide an opportunity to investigate the long-term health effects attributable to neonatal oxygen exposure. Using this mouse model of "modernera" BPD, we studied lung function and lung vascular structure in aging mice that were exposed to short-term hyperoxia as neonates.…”

Neonatal Hyperoxia Stimulates the Expansion of Alveolar Epithelial Type II Cells

“…Although vascular changes were not observed at this age, microvessel pruning and rarefaction, cardiac hypertrophy, and reduced survival were observed by 1 year of age (22). Analogous to children born prematurely, young adult mice exposed to hyperoxia as neonates also exhibit an altered host response to influenza A virus infection (21,23,24). Because this model of neonatal hyperoxia phenotypically recapitulates human diseases attributed to prematurity, it may provide an opportunity to understand how a high-oxygen environment at birth permanently alters lung development.…”

Endothelial Colony‐Forming Cells in Young Adults Born Preterm: A Novel Link Between Neonatal Complications and Adult Risks for Cardiovascular Disease

“…In addition, the mechanisms linking hypertension and ECFC dysfunction are still unknown. Beyond the hypothesis of a cause/effect relationship between ECFC dysfunction and elevated blood pressure, ECFC dysfunction and hypertension may result from common physiopathological pathways, such as the activation of the autonomic nervous system, renin–angiotensin system, and inflammation,45 which in turn were all previously shown to be altered in preterm‐born subjects or in experimental models of preterm birth 46, 47, 48, 49, 50, 51, 52, 53. These observations suggest that both ECFC dysfunction and elevated blood pressure could be long‐term consequences of very preterm birth.…”