Lung surfactant in the hyperinsulinemic fetal monkey.
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Biomedical subjects
Publications and source records attributed to J B Warshaw.
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During the perinatal period metabolic adaptations take place which insure that substrates for energy production and growth are available in the immediate postnatal period. The fetus receives a constant infusion of glucose, fatty acids and protein by the placenta. Late in gestation the accumulation of storage fuels such as glycogen and adipose tissue anticipate the abrupt cessation of substrate supply from the placenta at the time of birth. Postnatally an increase in endogenous production of glucose in the form of glycogenolysis and gluconeogenesis become important for maintenance of glucose homeostasis. Increase utilization of fatty acids in ketone bodies as energy substrates also become important in the postnatal period. These metabolic adaptations are mediated by the development of new enzyme activities as well as by changes in hormonal millieu and substrate availability.
The effect of exposure to high O2 concentration on neonatal rat lung oxidative function was determined. The water content of lungs from neonatal rats exposed to 100% O2 for the first 6 days of life was 3% greater than room-air control, indicating minimal pulmonary edema. Since neonatal rat lungs exposed to O2 have minimal pulmonary edema, they provide a model to determine the direct effect of O2 on mitochondrial oxidative function. After 6 days of exposure to 100% O2, lactate production by lung slices of neonatal rats was twofold greater than room-air controls. Lactate production by lung slices of neonatal rats exposed to six days of O2 and then 3 days of room air was equal to controls. Total pyruvate dehydrogenase activity was 45% lower in O2-exposed lung compared with control, and active pyruvate dehydrogenase activity was 20% lower. The oxidation of lauric acid, acetate, and beta-hydroxybutyrate was 40% lower in the O2-exposed lung compared with controls. These data suggest that there is a toxic effect of O2 on mitochondrial oxidative function in the absence of severe pulmonary edema and that these toxic effects are reversible within 72 h.
Bayley developmental assessments were performed at 12 months corrected age on 11 preterm infants, all of whom had undergone 133-Xenon cerebral blood flow measurements (CBF) on the 1st day of life and neonatal computerized tomography scans for the detection of intraventricular hemorrhage. The Bayley mental index was found to vary as a quadratic function of CBF to the left hemisphere, with moderate CBF values associated with more favorable outcomes than either low or high CBF values.
Placental glycogen metabolism was investigated in rat pregnancies complicated by streptozotocin-induced diabetes mellitus. Both diabetic and control placentas had increasing glycogen concentration from day 14 to day 16, after which glycogen concentration declined rapidly. The diabetic placentas had significantly elevated glycogen concentration when compared to controls from day 16 through term (day 22). Near term, when control glycogen content fell close to zero, the diabetic placentas still had appreciable glycogen levels. Total phosphorylase activity in the diabetic placentas was significantly higher than control values from day 16-22. Phosphorylase A activity, however, was lower in the diabetic placentas late in gestation, corresponding to the increased glycogen concentration seen at that time. Diabetic placentas had increased total synthase activity on the final 3 days of gestation, although synthase A activity was lower than corresponding control values. The placentas in this model are markedly increased in size late in gestation. No difference in protein concentration or protein/DNA ratio was noted. Total DNA content per placenta was significantly increased in the diabetic placentas after day 16 when compared to controls. Placental DNA in the diabetics continued to increase until day 18-19 of gestation, whereas DNA content in control placentas remained constant after day 16. Thus, the diabetic placentas apparently continue the process of DNA replication after DNA synthesis is complete in the controls.
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The developmental profile of pulmonary glycogen was investigated in fetuses of rats made diabetic before conception with the injection of 40 mg/kg streptozotocin. Lungs of control litters showed increasing pulmonary glycogen concentration from day 16-20, followed by significant decline by term (= 22 days). In contrast, the diabetic litters, which had pulmonary glycogen concentration equal to controls until day 20, showed significantly higher glycogen values (P less than 0.01) on days 21 and 22, consistent with a delay in glycogen degradation. This coincided with the finding of decreased amounts of fetal pulmonary phosphatidylcholine and disaturated phosphatidylcholine on day 21 of the diabetic gestation (P less than 0.05), but not before that time. Pulmonary glycogen phosphorylase A activity was significantly decreased in the diabetic litters on the final days of gestation, at the same time that the delay in glycogen breakdown became evident. Pulmonary glycogen synthase activity did not differ in the control and diabetic fetuses. The delay in pulmonary glycogen degradation seen in the fetus of the diabetic gestation is thus temporally related to the delay in lung maturation seen in this model and may be secondary to a decrease in the activity of the glycogenolytic enzyme phosphorylase A. Decreased availability of pulmonary glycogen stores for surfactant synthesis may be important in elucidating the mechanism of the delayed pulmonic maturation seen in fetuses of diabetic pregnancies.
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Changes in the pattern of neonatal bacterial infection in a 50-year period at one institution are documented, as well as the striking decrease in mortality during this period.
The effects of parenteral vitamin E treatment on aspects of the pulmonary biochemical and morphologic response to 100% oxygen were studied in newborn rabbits manifesting chemical evidence of vitamin E deficiency. Pups treated with 2 mg/100 g body weight increased serum vitamin E levels from 0.39 to 2.17 mg/dl by 72 hr and lung tissue vitamin E content from 3.52 to 17 mg/mg wet weight of lung. In vitro lipid peroxidation in lung homoginates of animals in 100% oxygen for 72 hr was inhibited by approximately 80% in animals receiving 100% oxygen plus vitamin E. Hyperoxia-induced increases in the pulmonary antioxidant enzymes, superoxide dismutase, glutathione peroxidase, and glutathione reductase were diminished by vitamin E administration. Lungs from vitamin E-treated animals did not show the early lung epithelial injury seen in animals exposed to 100% oxygen but not treated with vitamin E. Mophometric analysis of lungs of animals in room air for 72 hr showed 81.6% of lung to be normal as compared with 43.3% normal lung in the group maintained in 100% oxygen for 72 hr. In the group treated with oxygen plus vitamin E, the lungs were similar to room air controls (82.6% normal). This study thus provides further evidence for a direct antioxident affect of vitamin E in lung.
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We have carried out studies using rat lung slices showing that the developing lung utilizes both glucose and fatty acids as oxidative substrates. Glucose oxidation to CO2 decreased at birth but showed higher activity after weaning. The activity of the pentose phosphate pathway also decreased postnatally. In contrast to glucose, the oxidation of palmitate and caprate to CO2 showed an increase in the immediate postnatal period. Cytochrome oxidase and carnitine palmitoyltransferase showed a parallel postnatal increase following the increase in fatty acid oxidation. Cytochrome oxidase activity in adult lung was approximately 30% of peak newborn values. Palmitate incorporation into total lipids was greatest at 18 to 19 days of fetal development, at which time the lung content of nonesterified fatty acids was highest.
We have compared fluorescent and nonfluorescent light sources for phototherapy for newborn infants with hyperbilirubinemia. Phototherapy was provided by a tungsten halogen lamp and conventional fluorescent light with identical radiant flux of 6 microW/sq cm. For 22 infants treated with the nonfluorescent lamp the mean duration of phototherapy was 33.77 hours and the mean reduction of bilirubin was 3.84 mg/100 ml/day. This did not differ significantly from infants treated with conventional fluorescent lights. The nonfluorescent light can be utilized for infants in incubators or on radiant warmers. These results provide additional support for the relationship between radiant flux as a practical measure of phototherapy dose and the clinical response of a reduction in serum bilirubin.
To investigate the presence of subtle narcotic depression following maternal narcotic analgesia, we have evaluated the effects of naloxone versus placebo in a double-blind parallel group study in 43 normal term newborn infants whose mothers had received routine narcotic analgesia within six hours prior to delivery. Infants were given either an intramuscular injection of 20 microgram/kg naloxone or 0.20 ml/kg placebo after determination of the one-minute Apgar score, and the following measurements were compared: Apgar scores at one and five minutes, capillary blood gas values at one, 60, 120, and 240 minutes, and neurobehavioral assessments at one, 4, and 24 hours. No adverse effects from naloxone were observed. Neither Apgar scores nor capillary blood gas determinations differed significantly between the two groups. Response to sound was significantly higher in the naloxone group at 24 hours. The alertness score was significantly higher for the naloxone group at one and four hours; the general assessment score for the naloxone group was significantly higher at four and 24 hours. Average scores of naloxone and placebo groups were also different at four and 24 hours of age. These data demonstrate that maternal narcotic analgesia may produce subtle changes in alertness and general behavior not reflected by Apgar scores or respiratory status, potentially reversible by administration of naloxone shortly following delivery.