Cyclic AMP-dependent protein kinase (PKA) gene expression is developmentally regulated in fetal lung

AbstractWe characterized the ontogeny of cAMP-dependent protein kinase (PKA) enzymatic activity and PKA subunit mRNA expression in developing lung. The lungs of fetal Sprague–Dawley rat pups were removed after 16, 18, or 20 days of gestation and at term. PKA activity was greatest in the 18- and 20-day gestation lungs. Tissue cAMP levels were lowest in the 16-day lungs and increased with lung maturity. We were able to detect only low levels of mRNA for the Cβ subunit of PKA by northern blot analysis of total lung RNA and we were able to detect mRNA for the RIβ and RIIβ subunits only by RT-PCR. Therefore, we limited our analysis of PKA subunit mRNA levels to those for Cα, RIα and RIIα. The mRNA levels for Cα, were highest in the 16-day lung, decreased at 18 and 20 days, were lower in the newborn and lowest in the adult lung. RIα mRNA levels were also highest at 16 days and lowest in the adult lung. However, RIIα mRNA levels were similar in the 18-day, 20-day and newborn lungs. Dexamethasone treatment of fetal lung explants resulted in a small decrease in RIα mRNA levels but was not associated with a change in PKA activity. We conclude that PKA activity and PKA subunit mRNA expression are developmentally regulated in fetal lung. Such regulation results in optimal PKA activity at the time of type II alveolar cell differentiation, presumably in preparation for air breathing. The absence of an effect of glucocorticoid on PKA activity suggests that glucocorticoids are not responsible for the increase in PKA activity which accompanies this critical time in lung maturation

Neurodevelopmental Outcomes in the Early CPAP and Pulse Oximetry Trial

BACKGROUND: Previous results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses. METHODS: Using a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age. RESULTS: The primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P = 0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P = 0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P = 0.046). CONCLUSIONS: We found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT ClinicalTrials.gov number, NCT00233324.