Long-term Effects of Recurrent Intermittent Hypoxia and Hyperoxia on Respiratory System Mechanics in Neonatal Mice

BACKGROUND: Premature infants are at increased risk for wheezing disorders. Clinically, these neonates experience recurrent episodes of apnea and desaturation often treated by increasing the fraction of inspired oxygen (FIO(2)). We developed a novel paradigm of neonatal intermittent hypoxia with subsequent hyperoxia overshoots (CIH(O/E)) and hypothesized that CIH(O/E) elicits long-term changes on pulmonary mechanics in mice. METHODS: Neonatal C57BL/6 mice received CIH(O/E), which consisted of 10% O(2) (1min) followed by a transient exposure to 50% FIO(2), on 10-minute repeating cycles 24hrs/day from birth to P7. Baseline respiratory mechanics, methacholine challenge, RT-PCR for pro- and anti-oxidants, radial alveolar counts (RAC), and airway smooth muscle (ASM) actin were assessed at P21 after 2-week room air recovery. Control groups were mice exposed to normoxia (N(X)), chronic intermittent hyperoxia (CIH(E)), and chronic intermittent hypoxia (CIH(O)). RESULTS: CIH(O/E) and CIH(E) increased airway resistance at higher doses of methacholine and decreased baseline compliance compared to N(X) mice. Lung mRNA for NOX2 was increased by CIH(O/E). RAC and ASM actin were not different between groups. CONCLUSIONS: Neonatal intermittent hypoxia/hyperoxia exposure results in long-term changes in respiratory mechanics. We speculate that recurrent desaturation with hyperoxia overshoot may increase oxidative stress and contribute to wheezing in former preterm infants.