The Contribution of Intermittent Hypoxemia to Late Neurological Handicap in Mice with Hyperoxia-Induced Lung Injury

Abstract

Bronchopulmonary dysplasia (BPD) is considered by many to be an independent risk factor for poor neurodevelopment in premature infants. However, infants with BPD experience intermittent hypoxic episodes. This study was undertaken to determine whether intermittent hypoxic stress associated with BPD contributes to the development of neurological deficit. The model of BPD was produced in neonatal mice by exposure to hyperoxia (65% O₂) for 4 weeks. Arterial blood gases, pulmonary mechanics, and histopathology were used to define the degree of lung injury. The mice were subjected to brief (10 min/day) and intermittent (10 days) hypoxic stress (8% O₂) at different stages of the development of hyperoxia-induced lung injury. At 8 weeks of life, the neurofunction was assessed by water maze and rota-rod tests followed by cerebral morphological analysis using Nissl, bromodeoxyuridine, and caspase-3 immunostaining. Data were compared to naïve normoxic littermates and those mice that were exposed only to hyperoxia or intermittent hypoxia alone. Mice with BPD subjected to brief/intermittent hypoxia demonstrated a significantly poorer navigational memory performance as compared with normoxic mice and mice with BPD that were not subjected to intermittent hypoxia. The neurofunctional handicap in these mice was associated with significantly decreased brain weight and increased cerebral expression of caspase-3. Our results suggest that intermittent hypoxia associated with hyperoxia-induced lung injury, but not lung injury itself, results in significant neurological handicap in neonatal mice with BPD.

Mitochondrial Dysfunction Contributes to Alveolar Developmental Arrest in Hyperoxia-Exposed Mice

“…We used hyperoxia to induce BPD-like changes in immature mice. After 4 weeks of hyperoxia (65% or 85% O 2 ), mice exhibit histologic and functional changes seen in human neonates with BPD: decreased alveolarization, respiratory acidosis, increased lung resistance, and decreased lung compliance (11,21). Because alveolarization in mice is completed by 2 to 3 weeks of postnatal age (12), we shortened hyperoxic exposure to 2 weeks.…”

“…In this study, mice exposed to pyridaben for 2 weeks demonstrated a significantly (P 5 0.03) decreased body weight (6.12 6 0.99 g versus 7.39 6 0.52 g) and significantly greater mortality rate (chi square P 5 0.04) compared with their vehicle-treated controls. Similarly, hyperoxia-induced lung injury is associated with poor weight gain and significantly higher mortality rates (11,21). Thus, the same phenotype-an arrested alveolarization, pulmonary mitochondrial dysfunction, and retarded growth-has been induced by two distinctively different experimental challenges (exposure to hyperoxia or pyridaben).…”

“…The model of BPD was produced in 3-day-old (Postnatal Day [P]3) neonatal mice as described (11) with minor modification. P3 mice (C57Bl/6J) with their dams were purchased from Jackson Laboratories (Bar Harbor, ME).…”

Intratracheal transplantation of mesenchymal stem cells simultaneously attenuates both lung and brain injuries in hyperoxic newborn rats

“…ronchopulmonary dysplasia (BPD), a chronic lung disease that occurs in premature infants receiving prolonged ventilator support and oxygen supplementation, is associated with an increased risk of long-term neurodevelopmental impairments (1). Despite its limited predictive value, some clinical studies have also identified BPD as an independent risk factor for the development of neurofunctional deficits in premature infants, including cerebral palsy and developmental retardation, even in the absence of catastrophic brain injuries such as intraventricular hemorrhage and hypoxic-ischemic encephalopathy (1)(2)(3).…”

“…Despite its limited predictive value, some clinical studies have also identified BPD as an independent risk factor for the development of neurofunctional deficits in premature infants, including cerebral palsy and developmental retardation, even in the absence of catastrophic brain injuries such as intraventricular hemorrhage and hypoxic-ischemic encephalopathy (1)(2)(3). No specific or effective treatment is currently available for the preterm infant brain.…”