There is growing evidence that many childhood and adult diseases can be linked to environmental exposures during critically important stages of growth and development. Being born prematurely is a prime example of how the environment can adversely affect health later in life. Infants born prematurely have underdeveloped lungs that are not prepared to breath oxygen. They may also be exposed to excess oxygen used therapeutically to reduce tissue hypoxia and this can lead to bronchopulmonary dysplasia (BPD), a chronic lung disease seen in preterm infants needing supplemental oxygen. While many preterm infants eventually leave the hospital, they often suffer as children and adolescents from a variety of persistent pulmonary diseases (PPD), including reduced lung function and increased respiratory viral infections. Thus, there is an urgent need to understand how oxygen exposure at birth permanently disrupts lung development in preterm infants and how these persistent changes affect health and wellbeing later in life. To address this need, we developed a novel model by which mice are exposed to hyperoxia as neonates, recovered in room air, and then challenged with influenza A virus or bleomycin as adults. Analogous to children born prematurely, adult mice exposed to neonatal hyperoxia exhibit reduced lung function, mild alveolar simplification associated with reduced numbers of alveolar epithelial type II cells, learning deficits, and age- related hypertension. When infected with influenza A virus or administered bleomycin, adult mice exposed to neonatal hyperoxia displayed increased inflammation and fibrotic disease compared to siblings exposed to room air as neonates. While investigating how early-life oxygen exposure alters alveolar epithelial development, we discovered the oxygen environment at birth affects the expansion of type II cells. Relative to what is observed in room air, alveolar epithelial type II cell expansion is higher when mice are birthed into low (<17%) or high (e60%) oxygen. This implies type II cell proliferation occurs optimally under low oxygen tensions, such as in the fetus, is reduced when exposed to room air levels at birth, and increases again at high oxygen tensions. This increased number of type II cells is then excessively pruned when mice are returned to room air. Because type II cells play an important role in innate immunity and function as progenitor cells following epithelial injury, their depletion could be responsible for altering how the lung responds to alveolar epithelial injury. Here, we test the hypothesis that the oxygen environment at birth controls proper expansion of type II cells, which are necessary to protect the adult lung from alveolar epithelial injury. Understanding how the transition to the oxygen environment at birth controls proper expansion of alveolar epithelial type II cells is important because it could lead to new opportunities for identifying and treating children born prematurely who are at risk for PPD.

Public Health Relevance

Oxygen exposure in preterm infants has been associated with permanent changes in lung development and altered host response to respiratory viral infections later in life. Hence, understanding how the transition to an oxygen environment at birth affects alveolar epithelial cell development and provokes fibrotic lung disease in adult mice infected with influenza A virus or administered bleomycin could provide valuable insight into why children born prematurely are at risk for persistent pulmonary disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL091968-05A1
Application #
8630581
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
2008-04-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$345,375
Indirect Cost
$120,375
Name
University of Rochester
Department
Pediatrics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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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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