Bronchopulmonary dysplasia (BPD) is a chronic lung disease seen in premature infants requiring oxygen supplementation and ventilation. Although the use of exogenous surfactant and mild ventilation strategies has reduced mortality, infants who leave the hospital continue to exhibit reduced lung function even as adolescents. They are also more likely to develop asthma, be sensitive to second hand cigarette smoke, and be re-hospitalized when infected with respiratory viruses. Since these findings suggest BPD never fully repairs, there is an urgent need to understand how oxygen supplementation permanently disrupts lung development and how these changes enhance susceptibility to respiratory insults. To address this need, we developed a mouse model to understand how short-term oxygen exposure disrupts lung development and alters the response to influenza A virus infection, a common respiratory virus often encountered by age 2 in humans. Like children born prematurely, adult mice exposed to high oxygen (hyperoxia) as newborns had altered lung compliance that was attributed to increased alveolar simplification and disrupted epithelial cell differentiation. When infected with influenza A virus, these mice showed persistent inflammation, altered T cell responses, fibrosis, and increased mortality compared to infected mice that had been exposed to room air at birth. Because viral clearance was also delayed, we hypothesize that high oxygen supplementation to the developing lung increases susceptibility to infection by disrupting the host's ability to effectively clear respiratory viruses. Preliminary studies have identified three possible mechanisms by which changes in respiratory epithelial development could affect innate and adaptive immune responses to viral infection. While investigating these mechanisms in mice, viral clearance and ability to mobilize an appropriate immune response will be investigated in children born prematurely that received high oxygen supplementation. By integrating research findings in mice and humans, we hope to ultimately identify novel therapeutic opportunities for improving the health of children born prematurely.

Public Health Relevance

/ RELEVANCE TO PUBLIC HEALTH Exposure of premature infants to high oxygen supplementation disrupts lung development, and is associated with long-term deficits in lung function and increased susceptibility to respiratory infections. By integrating research findings obtained from influenza virus infected adult mice exposed to neonatal hyperoxia with immune responses in infected children born prematurely, we hope to ultimately identify novel therapeutic opportunities for improving the health of children born prematurely.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL097141-05
Application #
8511512
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M2))
Program Officer
Blaisdell, Carol J
Project Start
2009-09-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$458,389
Indirect Cost
$161,697
Name
University of Rochester
Department
Pediatrics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Boule, Lisbeth A; Winans, Bethany; Lambert, Kris et al. (2015) Activation of the aryl hydrocarbon receptor during development enhances the pulmonary CD4+ T-cell response to viral infection. Am J Physiol Lung Cell Mol Physiol 309:L305-13
Reilly, Emma C; Martin, Kyle C; Jin, Guang-bi et al. (2015) Neonatal hyperoxia leads to persistent alterations in NK responses to influenza A virus infection. Am J Physiol Lung Cell Mol Physiol 308:L76-85
Winans, Bethany; Nagari, Anusha; Chae, Minho et al. (2015) Linking the aryl hydrocarbon receptor with altered DNA methylation patterns and developmentally induced aberrant antiviral CD8+ T cell responses. J Immunol 194:4446-57
Wheeler, Jennifer L H; Martin, Kyle C; Resseguie, Emily et al. (2014) Differential consequences of two distinct AhR ligands on innate and adaptive immune responses to influenza A virus. Toxicol Sci 137:324-34
Regal, Jean F; Lawrence, B Paige; Johnson, Alex C et al. (2014) Neonatal oxygen exposure alters airway hyper-responsiveness but not the response to allergen challenge in adult mice. Pediatr Allergy Immunol 25:180-6
Maduekwe, Echezona T; Buczynski, Bradley W; Yee, Min et al. (2014) Cumulative neonatal oxygen exposure predicts response of adult mice infected with influenza A virus. Pediatr Pulmonol :
Yee, Min; Buczynski, Bradley W; O'Reilly, Michael A (2014) Neonatal hyperoxia stimulates the expansion of alveolar epithelial type II cells. Am J Respir Cell Mol Biol 50:757-66
Jin, Guang-Bi; Winans, Bethany; Martin, Kyle C et al. (2014) New insights into the role of the aryl hydrocarbon receptor in the function of CD11c⁺ cells during respiratory viral infection. Eur J Immunol 44:1685-98
Boule, Lisbeth A; Winans, Bethany; Lawrence, B Paige (2014) Effects of developmental activation of the AhR on CD4+ T-cell responses to influenza virus infection in adult mice. Environ Health Perspect 122:1201-8
Yee, Min; Buczynski, Bradley W; Lawrence, B Paige et al. (2013) Neonatal hyperoxia increases sensitivity of adult mice to bleomycin-induced lung fibrosis. Am J Respir Cell Mol Biol 48:258-66

Showing the most recent 10 out of 23 publications