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A2322 - Effect of Variable Oxygen Tensions on Mast Cell Hyperplasia in Neonatal Lung Disease
Author Block: A. Savage1, B. Summers1, S. Worgall2, R. B. Silver1; 1Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, United States, 2Department of Pediatrics, Weill Cornell Medicine, New York, NY, United States.
RATIONALE: Premature birth is associated with bronchopulmonary dysplasia (BPD) and linked to long-term abnormalities in lung function. The causes of BPD are unknown, but may result from inflammation-mediated injury that is worsened by supplemental oxygen, an intervention necessary for survival. We previously demonstrated, in a murine model of BPD, that severe levels of supplemental oxygen lead to a significant and sustained increase in lung mast cells that underlie alveolar simplification and lung dysfunction. Mast-cell-deficiency was protective. Using a similar model we undertook experiments to determine if moderate and mild neonatal hyperoxia, more closely mimicking current clinical practice in the care of premature infants, leads to a phenotype of alveolar simplification. We hypothesize that wide ranges of neonatal hyperoxia lead to irreversible changes in the lung architecture and mast cell hyperplasia that continue during the relative hypoxia (normoxia) subsequent to the high oxygen. Experiments were also performed to determine whether prenatal inflammation in combination with neonatal hyperoxia leads to a more pronounced phenotype. METHODS: Neonatal mice (P0) were subjected to hyperoxia for 2 weeks, followed by a return to room air for an additional 3 weeks. The mice were exposed to 80% (severe), 45% (moderate), and 30% (mild) O­2. Pups from dams injected with intraperitoneal endotoxin (LPS) and exposed to neonatal hyperoxia were also studied. Airway reactivity in response to methacholine and lung histology were analyzed. RESULTS: In neonatal hyperoxia the increase in the alveolar chord length continues during room air recovery. Like that observed previously with 80% O2, the lung mast cell population increases in mild and moderate hyperoxia and continues during the return to normoxia. The number of mast cells and the chord length are correlated to the magnitude of neonatal hyperoxia. In 5-week old mice exposed to prenatal inflammation and neonatal hyperoxia (80%) the lung mast cell population and alveolar chord length increased. Additionally, the combination of the prenatal inflammation with neonatal hyperoxia increased airway reactivity and caused airway remodeling. CONCLUSIONS: These data suggest that neonatal hyperoxia alone induces defective alveolarization and mast cell hyperplasia over a wide range of oxygen levels. We observe continued changes in lung structure and function during the period of “relative hypoxia,” with the change from high to normal oxygen. The addition of prenatal inflammation, which mimics maternal infection, also leads to bronchial hyper-reactivity. The combination of prenatal inflammation and neonatal hyperoxia causes a lung phenotype that includes features of asthma and emphysema.