Acute and chronic changes in the control of breathing in a rat model of bronchopulmonary dysplasia

Abstract

Infants born very prematurely (<28 weeks gestation) have immature lungs and often require supplemental oxygen. However, long‐term hyperoxia exposure can arrest lung development leading to bronchopulmonary dysplasia (BPD), which increases acute and long‐term respiratory morbidity and mortality. The neural mechanisms controlling breathing are highly plastic during development. Whether the ventilatory control system adapts to pulmonary disease associated with hyperoxia exposure in infancy remains unclear. Here, we tested the hypothesis that there would be age‐dependent adaptations in the control of breathing in an established rat model of hyperoxia‐induced BPD. Hyperoxia exposure (FIO2: 0.9 from 0–10 days of life) led to a BPD‐like lung phenotype, including sustained reductions in alveolar surface area and counts, and modest increases in airway resistance. Hyperoxia exposure also led to chronic increases in room air and acute hypoxic minute ventilation (VE) and age‐dependent changes in breath‐to‐breath tidal volume and breathing frequency variability. Hyperoxia‐exposed rats had normal hypoxic ventilatory responses, oxygen saturation (SpO2) in room air, but greater reductions in SpO2 during acute hypoxia (12% O2) indicating reduced hypoxic sensitivity and/or hypoventilation due to diseased lungs. However, VE was increased indicating an increase in respiratory drive. Perinatal hyperoxia led to greater glial fibrillary acidic protein expression and an increase in neuron counts within 6 of 8 and 1 of 8 key brainstem regions controlling breathing, respectively, suggesting astrocytic expansion. In conclusion, perinatal hyperoxia in rats induced a BPD‐like phenotype and age‐dependent adaptations in VE that may be mediated through changes to the neural architecture of the ventilatory control system. Our results suggest chronically altered ventilatory control in BPD. Support or Funding Information Children's Research Hospital of Wisconsin Research Institute, NIH R01 HL 122358, & Parker B. Francis Foundation This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mortality and ventilatory effects of central serotonin deficiency during postnatal development depend on age but not sex

“…Ventilation in neonatal rats was measured using a custombuilt, 200mL Plexiglass plethysmograph as described previously (Kaplan et al, 2016;Mouradian et al, ,2012Mouradian et al, , , 2019. Briefly, the gas inflow rate (150 ml/min) was balanced at the same or slightly lower than outflow vacuum rates to prevent CO 2 accumulation and assure rapid gas exchange.…”

“…All data collected were analyzed offline using LabChart Pro Software as described previously (Mouradian et al, 2019). In brief, each study was recorded in its own file, opened in LabChart, and two additional channels were added to measure the voltage deflection from peak to valley of each respiratory cycle (tidal volume) and the rate of respiratory cycles (breathing frequency).…”

Current evidence and outcomes for retinopathy of prematurity prevention: insight into novel maternal and placental contributions

“…Although such efforts are gradually delineating the best practices for maximizing preterm infant visual outcomes, there is yet no clinical consensus regarding protocols and target ranges for preterm oxygen therapy, which is particularly true in developing countries with the greatest disease burden [4,[54][55][56]. Various co-morbidities that impact systemic oxygenation such as bronchopulmonary dysplasia [57,58], thrombocytopenia [59], and anemia [60,61] are also associated with ROP development and/or severity. Interventions targeting these co-morbid conditions, such as transfusion, often show association with more severe ROP disease, though this is likely a surrogate indicator of hypoxia as the etiologic factor [62].…”

Maternal Tn Immunization Attenuates Hyperoxia-Induced Lung Injury in Neonatal Rats Through Suppression of Oxidative Stress and Inflammation

“…Prolonged exposure of neonatal rodents to hyperoxia resulted in decreased alveolar septation and increased terminal air space size, similar to human bronchopulmonary dysplasia (3, 4). Despite early surfactant therapy, optimal ventilation strategies, and increased use of noninvasive positive pressure ventilation, bronchopulmonary dysplasia remains a major cause of morbidity and mortality during the first year of life, and many infants experience significant respiratory morbidity, including decreased response to acute hypoxia, increased airway reactivity, and development of obstructive airway disease throughout childhood (5–7). No effective clinical therapy is currently available to prevent the development and long-term pulmonary sequelae of bronchopulmonary dysplasia.…”