) There is growing appreciation that prenatal and postnatal environmental factors shape our health later in life. One of the most profound environmental factors that the developing lung will ever experience is oxygen as it transitions at birth from a fetal to air environment. While the term lung is prepared to breathe oxygen, the preterm lung transitions into air too soon and is often exposed to excess oxygen used to maintain appropriate oxygen saturations. This aberrant oxygen exposure at birth increases the risk for long-term lung disease through poorly understood mechanisms. Our laboratory developed and uses a unique mouse model designed to understand how high levels of oxygen at birth increases the severity of influenza A virus (IAV) infections in adults. Studies conducted during the previous funding period established that neonatal hyperoxia accelerates proliferation of alveolar epithelial type 2 cells (AEC2s), that these cells are slowly depleted when mice return to room air, and that the loss of AEC2s contributes to fibrotic lung disease when the mice are infected with IAV. This proposal builds on these findings by investigating how the oxygen-dependent depletion of AEC2s enhances the severity of IAV infections. Using genetic lineage studies, we found that neonatal hyperoxia depletes AEC2s by stimulating their differentiation into alveolar epithelial type 1 cells (AEC1s), neonatal hyperoxia enhances death of AEC1s during IAV infection, and that many AEC1s in adult mice exposed to neonatal hyperoxia express Ki67, a proliferation marker traditionally used to mark cancer progression. Recent studies however show Ki67 does not regulate cell proliferation but rather modifies gene expression via its ability to organize heterochromatin. Because proliferating cells are hypersensitive to the genotoxic effects of hyperoxia and damaged cells can transmit that experience thorough epigenetic inheritance, we will test the hypothesis that neonatal hyperoxia enhances sensitivity to IAV infection by inducing Ki67-dependent epigenetic changes in proliferating AEC2s that are maintained when they differentiate into AEC1s.
Aim 1 uses novel Ki67-reporter and Ki67-null mice to determine whether AEC2s that proliferate during neonatal hyperoxia produce AEC1s that are marked by persistent Ki67 expression.
Aim 2 infects these mice with recombinant strains of IAV-expressing fluorescent protein used to determine whether Ki67 modifies how AEC1s respond to IAV infection.
Aim 3 uses cell-specific deep RNA sequencing and chromatin immunoprecipitation to determine whether Ki67 modifies a subset of oxygen-dependent changes in gene expression and that these changes help explain why AEC1s are susceptible to IAV infection. Understanding how neonatal hyperoxia shapes how AECs respond to IAV infection in mice is important because the scientific discoveries will stimulate development of therapies designed to improve the health of people born preterm.

Public Health Relevance

/ RELEVANCE TO PUBLIC HEALTH Preterm infants are often exposed to an inappropriate oxygen environment at birth that causes persistent lung disease later in life through poorly understood mechanisms. This application uses a unique mouse model to understand how excess oxygen at birth alters lung development and the host response to influenza A virus infection. The research is important because the scientific discoveries could stimulate development of new therapies designed to improve health of people born preterm.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Natarajan, Aruna R
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University of Rochester
School of Medicine & Dentistry
United States
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Morris-Schaffer, Keith; Sobolewski, Marissa; Welle, Kevin et al. (2018) Cognitive flexibility deficits in male mice exposed to neonatal hyperoxia followed by concentrated ambient ultrafine particles. Neurotoxicol Teratol 70:51-59
Yee, Min; Cohen, Ethan David; Domm, William et al. (2018) Neonatal hyperoxia depletes pulmonary vein cardiomyocytes in adult mice via mitochondrial oxidation. Am J Physiol Lung Cell Mol Physiol 314:L846-L859
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