Despite the use of exogenous surfactant, steroids, and mild ventilation, premature infants often require oxygen assistance and many develop bronchopulmonary dysplasia (BPD). BPD is the most common form of chronic lung disease in newborns and thought to be caused by oxidative stress that disrupts lung development. While many infants receiving oxygen or suffering from BPD eventually leave the hospital, they often exhibit reduced lung function even as adolescents. Moreover, recent epidemiologic studies indicate children who had been exposed to elevated oxygen at birth are more likely to have viral infections, asthma, increased sensitivity to second hand cigarette smoke, and more out-of-school sick days than children who were not exposed to oxygen. Thus, there is an urgent need to understand how oxidative stress permanently disrupts lung development in premature infants and how these changes enhance susceptibility to future respiratory insults. While investigating how hyperoxia disrupts lung development in neonatal mice, we identified a novel subpopulation of alveolar epithelial Type II cells that selectively expresses genes that destroy RNA viruses and bacteria, and control asymmetric cell division of stem/progenitor cells. This putative virus resistant subpopulation may be critical for alveolar repair following infection because Type II cells are trophic for influenza and other RNA viruses. Indeed, this subpopulation of Type II cells proliferated while other Type II cells died when mice were infected with influenza A virus. Moreover, adult mice exposed to hyperoxia as neonates have simplified lungs with fewer alveolar epithelial Type II and more Type I cells. These mice also exhibit significantly greater inflammation, fibrosis, and mortality when infected with influenza A virus. Based upon these findings, we propose to test the hypothesis that hyperoxia permanently disrupts alveolar lung development by stimulating the differentiation of alveolar epithelial Type II into Type I cells and this is associated with enhanced susceptibility to influenza virus due to loss of a virus-resistant subpopulation of Type II cells. By defining how hyperoxia affects alveolar epithelial cell differentiation, we hope to clarify how it disrupts neonatal lung development and why infants born prematurely continue to suffer from respiratory infections throughout life.

Public Health Relevance

/ RELEVANCE TO PUBLIC HEALTH Exposure of premature infants to high oxygen disrupts lung development, and has been associated with long-term deficits in lung function and increased susceptibility to respiratory infections. By defining how high oxygen disrupts alveolar epithelial cell differentiation in neonatal mice, we hope to clarify how it disrupts lung development and why infants born prematurely continue to suffer from respiratory infections throughout life.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091968-04
Application #
8197382
Study Section
Special Emphasis Panel (ZRG1-RES-B (03))
Program Officer
Lin, Sara
Project Start
2008-12-10
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
4
Fiscal Year
2012
Total Cost
$381,150
Indirect Cost
$133,650
Name
University of Rochester
Department
Pediatrics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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
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
Kalifa, Lidza; Gewandter, Jennifer S; Staversky, Rhonda J et al. (2014) DNA double-strand breaks activate ATM independent of mitochondrial dysfunction in A549 cells. Free Radic Biol Med 75:30-9
Bhattacharya, Soumyaroop; Zhou, Zhongyang; Yee, Min et al. (2014) The genome-wide transcriptional response to neonatal hyperoxia identifies Ahr as a key regulator. Am J Physiol Lung Cell Mol Physiol 307:L516-23
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
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
Zhao, Lan; Yee, Min; O'Reilly, Michael A (2013) Transdifferentiation of alveolar epithelial type II to type I cells is controlled by opposing TGF-* and BMP signaling. Am J Physiol Lung Cell Mol Physiol 305:L409-18
Buczynski, Bradley W; Maduekwe, Echezona T; O'Reilly, Michael A (2013) The role of hyperoxia in the pathogenesis of experimental BPD. Semin Perinatol 37:69-78
Buczynski, Bradley W; Yee, Min; Martin, Kyle C et al. (2013) Neonatal hyperoxia alters the host response to influenza A virus infection in adult mice through multiple pathways. Am J Physiol Lung Cell Mol Physiol 305:L282-90
Buczynski, Bradley W; Yee, Min; Paige Lawrence, B et al. (2012) Lung development and the host response to influenza A virus are altered by different doses of neonatal oxygen in mice. Am J Physiol Lung Cell Mol Physiol 302:L1078-87

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