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ABSTRACT: Fetuses of mothers with uncontrolled gestational diabetes have an increased risk of developing neonatal respiratory distress syndrome and are frequently hyperinsulinemic, thus it has been proposed that high levels of insulin delay fetal lung maturation. We have shown previously that insulin inhibits the accumulation of mRNA for the surfactant-associated proteins A and B (SP-A and SP-B) in human fetal lung explants maintained in vitro. To test the hypothesis that the inhibitory effects of insulin on the surfactant proteins are the result of a direct action of insulin on the lung epithelial cell, we evaluated the effects of insulin in the H441 cell line, a human pulmonary adenocarcinoma cell line that expresses SP-A and SP-B mRNA. We observed that insulin treatment for 48 h decreased SP-A mRNA and protein levels in a concentration-dependent manner when compared to controls. The inhibitory effect of insulin on SP-A mRNA levels was apparent as early as after 4 h of exposure. SP-B mRNA levels were also significantly decreased by insulin in a concentration-dependent manner. Insulin, at 2.5 microg/ml, inhibited SP-A gene transcription by approx. 67%, and inhibited SP-B gene transcription by about 32%. There was no significant effect of insulin on SP-A or SP-B mRNA stability. Thus, we have observed a pattern of insulin inhibition of SP-A and SP-B gene expression in the H441 lung epithelial cell line similar to that previously observed in human fetal lung explants, which are comprised of both epithelial and mesenchymal cells. Our findings provide further evidence that insulin may delay fetal lung maturation by inhibiting SP-A and SP-B gene expression. Furthermore, our findings suggest that the inhibitory effects of insulin are, at least partially, the result of a direct action on the lung epithelial cell.
Biochimica et Biophysica Acta 11/1998; 1442(1):60-70. · 4.66 Impact Factor
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ABSTRACT: Surfactant replacement therapy has been shown to be an effective and often life-saving treatment for newborn infants with respiratory distress syndrome (RDS). This article provides the clinician with an update regarding the various other applications of surfactant replacement therapy, as well as issues related to surfactant administration for the preparations approved for use in pediatric patients.
Pediatric Clinics of North America 07/1998; 45(3):549-72. · 2.24 Impact Factor
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ABSTRACT: Infants of diabetic mothers are frequently hyperinsulinemic and have an increased incidence of neonatal respiratory distress syndrome, a disease caused by a deficiency in the production of pulmonary surfactant by alveolar type II cells. It has been hypothesized that insulin inhibits fetal lung type II cell differentiation. We have shown previously that insulin inhibits the accumulation of surfactant protein (SP)-A and SP-B mRNA and has no effect on SP-C mRNA levels in human fetal lung tissue maintained in vitro. We hypothesized that treatment with glucocorticoids, which are used clinically to accelerate human fetal lung maturation, would overcome the inhibitory effects of insulin on human fetal lung development. In the present study, human fetal lung explants were maintained in the presence or absence of cortisol added alone, or in insulin plus cortisol added together. Cortisol significantly decreased SP-A mRNA levels by approximately 50% at the 100 nM concentration and significantly increased levels by approximately 20% at the 1 nM concentration. Cortisol increased SP-B and SP-C mRNA levels in a dose-dependent fashion (5- and 45-fold at 100 nM cortisol, respectively). The combination of 1 nM cortisol and insulin resulted in inhibition of mRNA levels for SP-A, SP-B, and SP-C at the high insulin concentrations (approximately 50% inhibition for SP-A and SP-B and approximately 25% inhibition of SP-C mRNA levels, in the presence of 40 pmol/L x 10(-3) insulin). Surprisingly, 100 nM cortisol plus inhibitory concentrations of insulin increased SP-A mRNA levels (2-fold at 40 pmol/L x 10(-3).(ABSTRACT TRUNCATED AT 250 WORDS)
Pediatric Research 11/1995; 38(4):513-21. · 2.70 Impact Factor
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ABSTRACT: Respiratory distress syndrome (RDS) is primarily caused by an immaturity in the synthesis and secretion of surfactant by the fetal lung type II cell. Fetal hyperinsulinemia associated with maternal diabetes places the newborn at an increased risk of developing RDS, and therefore, it has been hypothesized that insulin inhibits type II cell differentiation. We have previously shown that insulin inhibits the accumulation of surfactant-associated protein A (SP-A), the major surfactant-associated protein, in human fetal lung explants maintained in vitro. In the present study, we used Northern blot analysis to evaluate the effects of insulin on the content of SP-A messenger RNA (mRNA) as well as on the content of mRNA for the hydrophobic surfactant-associated proteins SP-B and SP-C in human fetal lung explants maintained in vitro. Lung explants were maintained in serum-free medium with or without added insulin (0.25-2500 ng/ml) for up to 6 days. We observed that insulin, at concentrations of 25-2500 ng/ml, significantly inhibited the accumulation of SP-A mRNA when compared to controls (P less than 0.01). The inhibitory effect of insulin on SP-A mRNA accumulation was dose dependent with an approximately 75% inhibition observed at 2500 ng/ml. Insulin, at the concentration of 2500 ng/ml, significantly inhibited the accumulation of SP-B mRNA by approximately 30% when compared to control levels (P less than 0.01) but had no effect at lower concentrations. Insulin had no significant effect on SP-C mRNA levels at any concentration tested. Our findings provide evidence that insulin may delay fetal lung development by inhibiting SP-A and SP-B gene expression. A deficiency of these proteins in pulmonary surfactant may account for the increased incidence of RDS in infants of diabetic mothers.
Endocrinology 09/1992; 131(2):669-76. · 4.46 Impact Factor
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ABSTRACT: Cases of fusiform bacteria sepsis have been reported infrequently in the pediatric literature. This case demonstrates the severe metastatic complications of fusiform bacterial sepsis including osteomyelitis, with multiple pathological fractures, sepsis, and abscesses of the liver. In the diagnostic evaluation of the etiology for this uncommon infection, child abuse was discovered in all children of this family. In children with uncommon infections and no underlying etiology, child abuse should be considered.
Clinical Pediatrics 10/1989; 28(9):423-5. · 1.15 Impact Factor
