Intra-amniotic interleukin (IL)-1 increases surfactant components in immature fetal lung, whereas high IL-1 after birth is associated with surfactant dysfunction. Our aim was to investigate whether the fetal age influences the responsiveness of surfactant proteins (SPs) to IL-1. Rabbit lung explants from fetuses at 19, 22, 27, and 30 d of gestation and 1-d-old newborns were cultured in serum-free medium in the presence of recombinant human (rh) IL-1alpha or vehicle. The influence of IL-1alpha on SP-A, -B, and -C messenger RNA (mRNA) content was dependent on the conceptional age. In very immature lung on Day 19, rhIL-1alpha (570 ng/ml for 20 h) increased SP-A, -B, and -C mRNA by 860+/-15%, 314+/-108%, and 64+/-17%, respectively. The increase in SP-A mRNA was evident within 4 to 6 h. IL-1alpha increased the SP-A concentration in alveolar epithelial cells and in the culture medium within 20 h. In contrast, at 27 to 30 d of gestation and in newborns, IL-1alpha decreased SP-C, -B, and -A mRNA by means of 64 to 67%, 48 to 59%, and 12 to 15%, respectively. SP-B protein decreased by 45 to 60%. The decrease in mRNA became evident within 8 to 12 h and was dependent on IL-1 concentration. On Day 27, IL-1alpha accelerated the degradation of SP-B mRNA in the presence of actinomycin D. IL-1 did not increase the degradation rate of SP-A mRNA unless both actinomycin D and cycloheximide were added to the explants. The present findings may explain some of the contrasting associations between inflammatory cytokines and lung diseases during the perinatal period. The determinants of the direction of the IL-1 effect on the expression of SPs remain to be identified.
Intra-amniotic lipopolysaccharide (LPS) and cytokines may decrease respiratory distress syndrome (RDS) and increase chronic lung disease in the newborn. The aim was to identify the primary inflammatory mediators regulating the expression of surfactant proteins (SP) in explants from immature (22-day-old fetus) and mature (30-day term fetus and 2-day-old newborn) rabbits. In immature lung, interleukin (IL)-1alpha and IL-1beta upregulated the expression of SP-A and SP-B. These effects of IL-1 were diminished, and SP-C mRNA was suppressed additively in the presence of tumor necrosis factor (TNF)-alpha and either LPS or interferon (IFN)-gamma. LPS, TNF-alpha, or IFN-gamma had no effect alone. In explants from the term fetus and the newborn, LPS, IL-1alpha, and TNF-alpha additively suppressed the SPs. LPS acutely induced IL-1alpha in alveolar macrophages in mature lung but not in the immature lung. IFN-gamma that generally has low expression in intrauterine infection decreased the age dependence of the other agonists' effects on SPs. The present study serves to explain the variation of the pulmonary outcome after an inflammatory insult. We propose that IL-1 from extrapulmonary sources induces the SPs in premature lung and is responsible for the decreased risk of RDS in intra-amniotic infection.
Spontaneous preterm birth due to intrauterine infection is associated with increased concentrations of cytokines in amniotic fluid and in the airways at birth. Intra-amniotic IL-1 induces fetal lung maturity, consistent with the decrease in the incidence of respiratory distress syndrome (RDS) in intrauterine inflammation. On the other hand, antenatal corticosteroid decreases the incidence of RDS in infants born prematurely. The aim of the present study was to investigate the interaction between IL-1 and glucocorticoid in the expression of the surfactant proteins SP-A, -B, and -C. Lung explants from rabbit fetuses at 22 (immature), 27 (transitional), and 30 ( The principal cause of RDS in newborns is surfactant deficiency due to immaturity of type II alveolar cells (1). Lung surfactant prevents atelectasis, contributes toward a decrease in alveolar edema and small airway closure, and is involved in pulmonary host defense. Apart from lipids, the complex contains specific SP that are bound to surfactant aggregates. SP-A is a hydrophilic C-type lectin, whereas SP-B and SP-C are hydrophobic membranous proteins. They all have highly specific roles in surfactant function (2, 3). Antenatal corticosteroid therapy given in the case of imminent premature birth decreases the incidence of RDS and intracranial hemorrhage (4).Glucocorticoids have been shown to influence the expression of SP in the fetal lung (5). In human fetal lung explants, Dx stimulated the expression of SP-A at low concentrations (Յ10 Ϫ8 M) and after short exposure (24 -48 h) or inhibited the expression of SP-A at higher doses as well as after longer exposure (3-4 d) (6 -8). The stability of SP-A mRNA decreased acutely after Dx (8, 9). In explants from rabbit lung, Dx (10 Ϫ7 M) decreased the rate of transcription of SP-A mRNA within 24 h, whereas the transcription rate was increased by Dx within 48 h (10). Both SP-B and SP-C were up-regulated by Dx in explants from mid-trimester human lung (11-13) and from fetal rabbit during the third trimester (14 -16), whereas SP-C was unaffected in 30-d-old fetal rabbit lung (17).Chorioamnionitis is the main setting associated with very premature birth. In this condition, the concentrations of IL-1␣ and IL-1 (18) and other cytokines (19) are increased in the amniotic fluid and in the airways shortly after birth (20). In very premature infants born due to intrauterine infection, the incidence of RDS is lower than could be expected on the basis of their very early birth (21). Premature infants who were more mature than in the series of Watterberg et al. (21) showed an increased incidence of RDS in intrauterine infection (22
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