Richard D. Zachman

Induction of choline phosphotransferase and lecithin synthesis in the fetal lung by corticosteroids.

Rabbit fetuses 23 to 24 days of gestation were injected with either 9-fluoroprednisolone acetate or saline. Three days later the lungs of steroid-treated animals showed a significant increase in lecithin concentration and cholinephosphotransferase activity. In addition, lung slices from these animals incorporated more [14C]choline into lecithin. The rise in enzyme activity and [14C]choline incorporation was blocked by prior treatment of fetuses with cycloheximide but not by treatment with actinomycin D. It is proposed that the corticosteroids induce de novo synthesis of the lung enzyme, which in turn leads to increased synthesis of lecithin through the choline incorporation pathway. Furthermore, it appears that the site of regulation involves translation of messenger RNA.

Relationship of vitamin A (retinol) status to lung disease in the preterm infant

Plasma concentrations of retinol and retinol-binding protein were measured at birth in 91 preterm infants. In 64% of these babies retinol values were less than 20 micrograms/dl, suggestive of vitamin A deficiency. Forty-seven of these infants were observed with sequential measurements of retinol and retinol binding protein through 21 days of age. In babies with respiratory distress syndrome retinol values were similar to those in babies without respiratory distress syndrome. The retinol binding protein levels were lower on the third day of life in babies with respiratory distress syndrome. Babies who developed bronchopulmonary dysplasia had lower concentrations of retinol at birth (P less than 0.05) and on day 21 (P less than 0.05) than did babies who did not develop bronchopulmonary dysplasia, despite receiving recommended intakes of vitamin A. Many preterm infants are deficient in vitamin A at birth, and failure to correct this deficiency may contribute to the development of chronic lung disease.

Role of Vitamin A in Lung Development

There is good rationale for presuming a role for vitamin A in lung development. In situ studies have demonstrated that certain retinoic acid (RA) receptor proteins are localized in a specific fashion during fetal lung branching and airway growth. Vitamin A stores are high in fetal lung and decrease toward term, possibly being utilized for changes in lung morphogenic remodeling. The binding activity, levels and expression of the cytosolic and nuclear receptor proteins for vitamin A undergo changes before and after birth in rat lung. RA slows fetal Type II cell proliferation in culture but stimulates choline incorporation into phosphatidylcholine. RA can regulate several other factors involved in lung development such as homeobox genes, matrix molecules and certain growth factors. Further study is needed on this potential functional role of RA in lung. Retinol deficiency results in lung histopathology that is similar to bronchopulmonary dysplasia, which occurs frequently in human premature neonates. Clinical trials are attempting to define the role of supplementation of vitamin A in the prevention and treatment of that condition.

Maternal smoking and respiratory distress syndrome

Infants of 603 patients on whom information about smoking habits during pregnancy was available were studied for incidence respiratory distress syndrome. Among the 360 patients who did not smoke, the incidence of respiratory distress syndrome in the neonate was 15.1%, whereas among patients who smoked, the incidence was 9.1%. We speculate that smoking produces a condition of chronic stress in the fetus which brings about an acceleration of fetal pulmonary maturation.

Incidence and treatment of the patent ductus arteriosus in the ill premature neonate

Abstract Two to 15 per cent of the patients admitted to a Neonatal Intensive-Care Unit developed signs of cardiac disease due to a PDA. In a four-year period, of 90 patients with a diagnosis of the PDA, confirmation was made in 44 (surgery, 27; autopsy, 12; and aortography, 5). Eighty per cent were 33 weeks gestation or less. Two-thirds of the patients went into congestive heart failure. Over 1 2 of these had severe respiratory distress and 44 per cent required a respirator. The diagnosis of a PDA and cardiac failure was made clinically by the presence of characteristic murmur frequently accompanied by a diastolic murmur, bounding pulses, hepatomegaly, apnea and bradycardia, roentgenographic evidence of perihilar edema and/or increased pulmonary vascularity, and an abnormal electrocardiogram. Twenty-seven patients underwent surgical ligation of the PDA. There were no deaths in the operating room. The survival rate in those over 1,000 grams was 80 per cent. Of those patients that died due to the PDA, nearly 60 per cent had bronchopulmonary dysplasia as an associated finding.

Perinatal Rat Lung Retinol (Vitamin A) and Retinyl Palmitate

ABSTRACT: The potential role for retinol (vitamin A alcohol) in the differentiation of the developing lung prompted this study in the perinatal rat. High performance liquid chromatography was used to separate, detect, and quantitate retinol and retinyl palmitate in lipid extracts of tissue and serum. Fetal and maternal blood showed the presence of retinol, whereas no retinyl palmitate was detected. On the other hand, fetal and postnatal lungs contained retinyl palmitate as well as retinol. Considerable changes in the content of lung retinyl palmitate were found during lung development. Fetal lungs (17-21 days of gestation) contained 2.3 ± 0.36 μg/g wet weight (mean ± SD) of retinyl palmitate and 0.14 ± 0.05 μg/g of retinol. Lungs of pups (1-10 days old) contained much less retinyl palmitate, 0.63 ± 0.20 μg/g, whereas the amount of retinol was the same as in fetal lungs. The surprisingly high content of retinyl palmitate in fetal lung and its depletion after birth may be functionally related to retinol action in the developing lung.

The effect of maternal ethanol ingestion on fetal rat heart vitamin A : a model for fetal alcohol syndrome

ABSTRACT: Ethanol consumption during pregnancy can cause fetal alcohol syndrome (FAS). Although the exact mechanism is unknown, nutritional alterations caused by ethanol exposure may be an etiologic factor in FAS. The congenital heart defects seen in FAS are similar to those found in vitamin A teratogenesis. Because ethanol ingestion alters vitamin A metabolism, we hypothesized that the cardiac manifestations seen in FAS result from an alteration in vitamin A metabolism or function in the developing fetus. Twenty-day gestation fetal rat hearts from ethanol-exposed and control pregnancies were analyzed for 1) levels of endogenous retinol, retinyl palmitate, and retinoic acid by quantitative HPLC; 2) binding activity levels of both retinol by cellular retinol binding protein and retinoic acid by cellular retinoic acid binding protein using specific competitive binding assays; and 3) relative abundance of cellular retinol binding protein and retinoic acid receptor α, β and γ subtype message as expressed in mRNA. Levels of retinol and retinyl palmitate were significantly higher (p < 0.01) and the level of retinoic acid was significantly lower (p < 0.02) in the ethanol-exposed fetal hearts. Binding activity levels of cellular retinol binding protein and cellular retinoic acid binding protein were not different in the two groups. The message for retinoic acid receptor α (3.7 kb) was increased (p < 0.01) and the message for retinoic acid receptor β was decreased (p < 0.05) in the ethanol-exposed hearts. The alterations in endogenous retinoid levels and changes in the expression of certain retinoic acid receptor subtypes indicate a modulation in vitamin A metabolism caused by maternal ethanol ingestion and suggests a role of vitamin A in the pathogenesis of FAS.

The Effect of Maternal Ethanol Ingestion on Fetal Vitamin A in the Rat

ABSTRACT: The effect of maternal ethanol ingestion on fetal tissue vitamin A was investigated. Pregnant rats were pair-fed control diets or diets containing 36% of energy as ethanol. After 17 or 21 d gestation, fetuses were removed and fetal and maternal tissues were analyzed by HPLC for retinol and retinyl palmitate. Ethanol consumption resulted in fewer fetuses per pregnancy, increased number of resorptions, and increased numbers of gross fetal abnormalities. In maternal tissues, ethanol consumption resulted in greater lung and kidney vitamin A concentrations. In the fetuses of ethanol-consuming pregnancies, free retinol in liver was higher at d 17. However, fetal liver palmitate levels and total retinyl palmitate in liver, lung, and kidney were lower in ethanol-fed rats at d 21 of gestation. Fetal lung retinyl palmitate concentrations were greater at both d 17 and d 21, and kidney levels were also greater at d 21. In conclusion, the ingestion of ethanol by pregnant rats is associated with a reduction in fetal liver vitamin A levels and an elevation in the levels of lung and kidney vitamin A, indicating possible altered vitamin A metabolism as a result of ethanol consumption.

Nasojejunal feedings in low-birth-weight infants.

Continuous nasojejunal and intermittent nasogastric feedings were compared in a controlled prospective study in 21 low-birth-weight infants. The groups were comparable in regard to period of gestation, birth weight, head circumference, and clinical findings. Cumulative weight gain, caloric and fluid intake, percent weight lost, blood chemistry values, and complications were used in evaluating the two groups. Upon completion of the 21-day study, N/J infants were found to have had statistically better weight gain, caloric intake, and fluid intake (p = 0.05-0.001) during the early part of the study. Weight loss was less in the N/J group (p less than 0.01). Neither group had abnormalities of blood chemistry or significant complications. It is concluded that N/J feeding in the low-birth-weight neonate is a safe, effective means of early nutritional intake, with advantages most pronounced during the first two weeks of life.

Retinoic acid and dexamethasone affect RAR-β and surfactant protein C mRNA in the MLE lung cell line

Lung development and surfactant biosynthesis are affected by retinoic acid (RA) and dexamethasone (Dex). Using a mouse lung epithelial cell line, we are exploring RA-Dex interactions through the study of RA and Dex effects on RA receptor (RAR) and surfactant protein (SP) C mRNA expression. RA increased expression of RAR-β (5.5 times) and SP-C (2 times) mRNA, with maximal effects at 24 h and at 10-6 M. The RA induction was not inhibited by cycloheximide, suggesting RA affects transcription. With added actinomycin D, RA did not affect the disappearance rate of RAR-β mRNA, but SP-C mRNA degradation was slowed, indicating an effect on SP-C mRNA stability. Dex decreased RAR-β and SP-C expression to 75 and 70% of control values, respectively, with greatest effects at 48 h and at 10-7 M. There was no effect of Dex on either RAR-β or SP-C mRNA disappearance with actinomycin D. However, cycloheximide prevented the effect of Dex. Despite Dex, RA increased both RAR-β and SP-C mRNA. This work suggests that RA and Dex affect RAR-β and SP-C genes by different mechanisms.