348 - Effects of hyperoxia and corticosteroids on newborn mouse lungs and brains continued into adulthood

Publication Number: 1332.348

Min J. Cho, Saint Louis University School of Medicine, Saint Louis, MO, United States; Emily X. Royse, Saint Louis University School of Medicine, St. Louis, MO, United States; Noah Hillman, Saint Louis University School of Medicine, St. Louis, MO, United States

Background: Extremely premature infants can develop bronchopulmonary dysplasia (BPD), characterized by alveolar simplification and lung inflammation, from mechanical ventilation and oxygen exposure. Postnatal corticosteroids can decrease the risk of BPD, but may increase the risk of poor neurologic development if used in infants not at high risk for BPD. Newborn mice are born at a stage of lung development similar to preterm infants, and brain development is similarly premature at birth. Mice at postnatal day 2 (P2) are in the saccular stage of lung development and pre-myelination in brain, whereas P7-9 mice are in the alveolar stage and have begun myelinating brain.

Objective: Utilizing a murine hyperoxia model of BPD, early (P2-4) and later (P7-9) postnatal steroid exposure were compared for changes in the brain at 14 days and in adulthood.

Design/Methods: Time-mated C57BL/6 pregnant females received intraperitoneal (IP) dexamethasone at E16 and then were allowed to deliver spontaneously. On P1, litters were randomized to either room air (RA) or 85% oxygen (Coy chamber) and mothers were rotated daily for 14 days. On P2, the litters were assigned to: 1) saline IP on P2 to P4; 2) dexamethasone 0.5 mg/kg (Dex) on P2 to P4; 3) Dex on P8 to P10; or 4) Dex on P2 to P4, P8 to P10 to make 8 groups. After 14 days, mice were either euthanized or allowed to grow in RA until age P80. Right lung and brain were fixed for histology and left lung and brain were frozen for RNA isolation. Histological examination of lungs and tissues were performed, and mRNA was analyzed for inflammation and injury.

Results: Both hyperoxia and Dex caused decreased weights and brain weights at 14 days (Table 1). Hyperoxia caused alveolar simplification (increased mean linear intercept [MLI]). Multiple courses of Dex increased MLI in RA mice, but decreased MLI in hyperoxia mice. In the lungs, hyperoxia increased IL-6 mRNA with no effects of dexamethasone, whereas in the brain late Dex or multiple courses of Dex decreased brain IL-6 mRNA. There were no differences in activated oligodendrocytes (OLIG+) in the brains. By 80 days, the mice had similar overall weights, but the brains were smaller in the Dex mice (0.459 g, p=0.04) and the 85% O2 mice (0.447 g, p=0.01) compared to saline/RA mice (0.481 g). There were no differences in lung simplification at 80 days though number of mice is low.

Conclusion(s): Both hyperoxia and dexamethasone can decrease lung and brain growth. Postnatal corticosteroids may modulate some hyperoxia changes in the lung and brain. Further cognitive testing is needed to determine if overall dexamethasone is beneficial to brain.

Table 1: Lung and Brain data at 14 days after steroids and/or hyperoxia