Long-Term Effects of Neonatal Hyperoxia in Adult Mice.

The outcomes of premature infants have improved greatly; however, the health risks in adulthood are still relatively unclear. Bronchopulmonary dysplasia (BPD) in premature infants is a major risk factor for alteration in lung function and predisposition to respiratory morbidity, and is associated with hyperoxia. The study explores the effect of neonatal hyperoxia on organ systems in adult mice. Newborn mouse litters were randomized to 85%O2 or room air (RA) on P3 for 12 days; mice were sacrificed at P3, P7, P15, 3 months and 9 months. Lungs were assessed by histopathology, radial alveolar count, mean linear intercept, and α-Smooth muscle actin immunohistochemistry. Aortic assessment included histology, wall thickness, elastin, and collagen content. Glomerular histology and nephron number were assessed in the kidneys. Hyperoxia-exposed mice had progressive alveolar simplification and poor weight gain over time. Greater thickness of pulmonary arterioles by 3 months and a higher Fulton index by 9 months suggest worsening pulmonary hypertension. Aortic wall thickness to lumen ratio was greater with a lower aortic elastin-to-collagen ratio suggesting long-term effects of neonatal hyperoxia. Hyperoxia-exposed mice at 9 months had smaller glomeruli as indicated by glomerular diameter and volume. Prolonged neonatal hyperoxia during the critical period of development induces irreversible lung damage, pulmonary hypertension and structural changes in the kidneys and aorta in adult mice. This could have implications for chronic adult diseases following exposure to high levels of oxygen in the newborn period. Anat Rec, 301:717-726, 2018. © 2017 Wiley Periodicals, Inc.

Neonatal hyperoxia increases airway reactivity and inflammation in adult mice.

BACKGROUND: Supplemental O2 to treat bronchopulmonary dysplasia (BPD) in premature infants, is a major risk factor producing alteration in lung function, airway reactivity, and predisposition to respiratory infections. This study explores inflammatory and airway responses following neonatal hyperoxia in adult mice. METHODS: Newborn mouse litters were randomized to 85% O2 or room air (RA) on P3 for 12 days; mice were sacrificed either on P15 or at 15 weeks following recovery in RA. Airway hyper reactivity (AHR) was assessed in vivo (8 and 12 weeks) and in vitro (15 weeks) with methacholine; Lung and BAL were assayed for inflammatory mediators, cell counts, CD3 immunohistochemistry, and histopathology. RESULTS: Hyperoxic mice had increased airway reactivity at baseline and following methacholine challenge in vivo (8 and 12 weeks); isolated tracheal rings had a significantly higher constriction response to methacholine in vitro compared to RA group. Inflammatory markers were higher at 2 weeks (MCP-1, IL-12, INF-γ) and at 15 weeks (LTB4 , VEGF); Lipoxin-A4 was lower in the hyperoxia group at both time points. Increased airway smooth muscle thickness and angiogenesis in the lung was seen at 15 weeks. Hyperoxic lungs exhibited alveolar simplification at 2 and 15 weeks. Absolute lymphocyte count was higher in lavage fluid with an increased CD3 cell count at 15 weeks suggesting persistent inflammation in adult mice following neonatal hyperoxia. CONCLUSIONS: Exposure to hyperoxia in newborn mice increases long-term airway reactivity with persistent lung inflammation associated with a marked increase in lymphocytes, suggesting long-term consequences in adults. Pediatr Pulmonol. 2016;51:1131-1141. © 2016 Wiley Periodicals, Inc.

Reoxygenation with 100% oxygen versus room air: late neuroanatomical and neurofunctional outcome in neonatal mice with hypoxic-ischemic brain injury.

Study investigated neuroutcome in mice subjected at 7-8 d of life to hypoxic-ischemic brain injury (HI) followed by 30 min of reoxygenation with 100% O(2) (Re-O(2)) or room air (Re-Air). At 24 h of recovery, mouse reflexes were tested. At 7 wks after HI spatial orientation and memory were assessed in the same mice. Mortality rate was recorded at 24 h and at 7 wks of recovery. In separate cohort of mice, changes in cerebral blood flow (CBF) during HI-insult and reoxygenation were recorded. Re-O(2)versus Re-Air mice exhibited significantly delayed geotaxis reflex. Adult Re-O(2)versus Re-Air mice exhibited significantly better spatial learning and orientation with strong tendency toward better preserved memory. Histopathology revealed significantly less hippocampal atrophy in Re-O(2)versus Re-Air mice. Following a hypoxia-induced hypoperfusion, Re-O(2) re-established CBF in the ipsilateral side to the prehypoxic level significantly faster than Re-Air. The mortality was higher among Re-O2 versus Re-Air mice, although, it did not reach statistical significance. Re-O(2)versus Re-Air restores CBF significantly faster and results in better late neuroutcome. However, greater early motor deficit and higher mortality rate among Re-O(2)versus Re-Air mice suggest that Re-O(2) may be deleterious at the early stage of recovery.