ABSTRACT
OBJECTIVE: To assess long-term pulmonary outcome of a regional cohort of children born at < 32 weeks' gestation compared with a matched term control group. STUDY DESIGN: All 125 surviving children born at 24 to 31 weeks' gestation during a 1-year period and a sociodemographically matched term control group were evaluated at age 7 years. RESULTS: Preterm children with previous bronchopulmonary dysplasia (BPD) were twice as likely to require rehospitalization during the first 2 years of life than were preterm children without BPD (53% vs 26%, P < .01). At 7 years of age the BPD group had more airway obstruction than did both preterm children without BPD and the term control group (significantly reduced mean forced vital capacity, forced expiratory volume in 1 second, and forced expiratory flow, 25% to 75% vital capacity, all, P < .001). Lung function among preterm children without previous BPD was similar to that of the term control group. Bronchodilator responsiveness was observed twice as often in preterm children with previous BPD (20 of 43, 47%) compared with preterm children without BPD (13 of 53, 25%) or the term control group (23 of 108, 21%, P < .001). These differences remained significant after adjustment was done for birth weight and gestational age. CONCLUSION: Preterm children without BPD demonstrate pulmonary function at school age similar to that of children in a healthy term control group, whereas preterm children with previous BPD demonstrate abnormal pulmonary function.
Subject(s)
Bronchopulmonary Dysplasia/physiopathology , Infant, Premature/growth & development , Respiratory Mechanics , Birth Weight , Child , Cohort Studies , Female , Gestational Age , Hospitalization , Humans , Infant, Newborn , Longitudinal Studies , Male , Prospective Studies , Respiratory Function TestsABSTRACT
Pulmonary surfactant, which is necessary for normal lung function, is under both developmental and hormonal regulation. Glucocorticoids induce all components of surfactant and have a unique biphasic effect on surfactant protein A (SP-A), either stimulating or inhibiting accumulation in cultured fetal lung depending on dose and time of exposure. In this study we further characterized glucocorticoid inhibition of SP-A in cultured explants of human fetal lung. Decreased content of SP-A mRNA was the dominant response to dexamethasone added either early or later during culture. Inhibition occurred at < or = 1 nM dexamethasone on prolonged exposure, was blocked by RU 486, and was observed with other glucocorticoids but not sex steroids. When cortisol was removed from the culture medium, inhibition was rapidly reversed. The immediate inhibitory effect of 100 nM dexamethasone on SP-A mRNA content was completely blocked in the presence of cycloheximide. SP-A gene transcription, measured by nuclear elongation assay, was decreased by 60% after 4- to 8-h exposure to 100 nM dexamethasone. Stability of SP-A mRNA, determined both by addition of actinomycin D and by label-chase experiments, was transiently decreased immediately after adding dexamethasone (t1/2 approximately 3 h). In tissue treated with dexamethasone for > or = 8 h the stability of SP-A mRNA in control and treated explants was not different (t1/2 approximately 8 h). Our findings indicate that inhibition of SP-A is the dominant response to glucocorticoid. This effect is receptor mediated and apparently involves induction of a labile protein(s) that decreases gene transcription and transiently reduces mRNA stability.
Subject(s)
Glucocorticoids/physiology , Lung/metabolism , Proteolipids/metabolism , Pulmonary Surfactants/metabolism , Cells, Cultured , Cycloheximide/pharmacology , Dactinomycin/pharmacology , Dexamethasone/pharmacology , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay , Fetus/cytology , Fetus/metabolism , Fetus/physiology , Gene Expression/genetics , Humans , Lung/embryology , Lung/physiology , Mifepristone/pharmacology , Proteolipids/analysis , Proteolipids/genetics , Pulmonary Surfactant-Associated Protein A , Pulmonary Surfactant-Associated Proteins , Pulmonary Surfactants/analysis , Pulmonary Surfactants/genetics , RNA, Messenger/genetics , Transcription, GeneticABSTRACT
Glucocorticoids increase expression of the genes for the pulmonary surfactant-associated proteins SP-B and SP-C in fetal lung both in vivo and in vitro. To examine the mechanism of these effects, we studied induction of SP-B and SP-C mRNAs in human fetal lung cultured as explants. Both mRNA levels rose rapidly in response to 100 nM dexamethasone (Dex), with a faster response for SP-B: maximal levels of induction were achieved in < or = 12 h for SP-B (3.5-fold versus control) versus approximately 24 h for SP-C mRNA (35-fold versus control). Cycloheximide (2.5 micrograms/ml) did not affect glucocorticoid induction of SP-B mRNA but markedly decreased induction of SP-C mRNA. In control cultures, cycloheximide did not significantly reduce levels of either transcript. In nuclear run-on assays, Dex increased the rate of gene transcription for both SP-B (2.8 +/- 0.3-fold versus control, n = 4) and SP-C (10- to 30-fold). Using actinomycin D to assess mRNA stability, the t1/2 of SP-B mRNA was increased from 7.5 +/- 0.4 h to 18.8 +/- 2.9 h by Dex treatment (P < 0.05), whereas the t1/2 of SP-C mRNA was not affected (9.3 +/- 1.7 h versus 8.1 +/- 1.2 h; NS). A similar increase in SP-B mRNA t1/2 with Dex (from 6 h to 19 h) was observed in label-chase studies with [3H]uridine. We conclude that glucocorticoids regulate the hydrophobic surfactant proteins of alveolar type II cells by different mechanisms: induction of SP-B is a primary response and includes an increase in both transcription rate and mRNA stability, whereas induction of SP-C is a secondary process, requiring ongoing protein synthesis, involving increased transcription rate without a change in mRNA stability.
