Decreased lung surfactant disaturated phosphatidylcholine in sudden infant death syndrome

The lipid composition of lung surfactant obtained by lung lavage at autopsy in 40 infants dying from the sudden infant death syndrome (SIDS), was compared to that obtained from 12 infants dying from other causes (control group). Analysis of the lipids from the two groups showed no major difference in the proportions of the various phospholipid classes particularly the predominant component, phosphatidylcholine (PC), which was present at 60.7 ± 0.9% (mean ± S.E.) of the total phospholipids in the SIDS group and 57.9 ± 2.9% in the control group. However the proportion of the PC present as the disaturated form (DSPC), was significantly (P < 0.01) reduced in the SIDS group (65.8 ± 1.6%) in comparison to the control group (77.4 ± 3.5%). The proportion of DSPC present in the PC fraction of SIDS infants in the high-risk age range of 1–26 weeks (63.9 ± 1.9%) was also significantly reduced (P < 0.01) in comparison to the total control group of infants. For infants older than 26 weeks, significant differences in the proportion of DSPC in PC were not observed between SIDS and control groups. A functional consequence of the observed reduction in the DSPC content of lung surfactant of SIDS infants could be a greater degree of fluidity of the surfactant, particularly at exhalation. Such a biophysical change in surfactant properties could have a profound influence on lung function and be a causative factor in sudden infant death.     

Decreased lung surfactant disaturated phosphatidylcholine in sudden infant death syndrome

The lipid composition of lung surfactant obtained by lung lavage at autopsy in 40 infants dying from the sudden infant death syndrome (SIDS), was compared to that obtained from 12 infants dying from other causes (control group). Analysis of the lipids from the two groups showed no major difference in the proportions of the various phospholipid classes particularly the predominant component, phosphatidylcholine (PC), which was present at 60.7 +/- 0.9% (mean +/- S.E.) of the total phospholipids in the SIDS group and 57.9 +/- 2.9% in the control group. However the proportion of the PC present as the disaturated form (DSPC), was significantly (P less than 0.01) reduced in the SIDS group (65.8 +/- 1.6%) in comparison to the control group (77.4 +/- 3.5%). The proportion of DSPC present in the PC fraction of SIDS infants in the high-risk age range of 1-26 weeks (63.9 +/- 1.9%) was also significantly reduced (P less than 0.01) in comparison to the total control group of infants. For infants older than 26 weeks, significant differences in the proportion of DSPC in PC were not observed between SIDS and control groups. A functional consequence of the observed reduction in the DSPC content of lung surfactant of SIDS infants could be a greater degree of fluidity of the surfactant, particularly at exhalation. Such a biophysical change in surfactant properties could have a profound influence on lung function and be a causative factor in sudden infant death.     

Fetal lung hypoplasia associated with maternal smoking: a morphometric analysis

Our recently reported animal (rat) model of maternal cigarette smoke exposure during pregnancy is characterized by fetal growth retardation and lung hypoplasia. We have further defined the fetal lungs using quantitative histologic techniques. Compared to controls, lung volume at term is reduced in the experimental animals (0.28 versus 0.33 ml, p less than 0.005). Saccules (fetal "alveoli") are reduced in number (3 X 10(6) versus 5.5 X 10(6), p less than 0.005) and increased in size (average saccular volume: 35 X 10(-9) versus 21 X 10(-9) ml, p less than 0.025). These changes in size and number are consequences of reduced formation of saccule partitions (septal crests) in the experimental lungs (volume density: 0.013 versus 0.018, p less than 0.025). Internal surface area is decreased in the hypoplastic lungs (161 versus 198 cm2, p less than 0.001). The total length of parenchymal elastic tissue is diminished (224 versus 354 M, p less than 0.05). In short the hypoplastic lungs contain fewer, larger saccules and the surface potentially available for gas exchange is reduced. These results show that maternal smoking in rats adversely modifies fetal lung growth. If these observations are applicable to humans, then reduced lung growth in children of smoking mothers may begin antenatally.     

Effects of neonatal high-dose short-term glucocorticoid treatment on the lung: a morphologic and morphometric study in the rat

Glucocorticoids are often applied in neonatology and perinatology to fight the problems of respiratory distress and chronic lung disease. There are, however, many controversies regarding the adverse side effects and long-term clinical benefits of this therapeutic approach. In rats, glucocorticoids are known to seriously impair the formation of alveoli when applied during the first two postnatal weeks even at very low dosage. The current study investigates short-term and long-term glucocorticoid effects on the rat lung by means of morphologic and morphometric observations at light and electron microscopic levels. Application of a high-dosage protocol for only few days resulted in a marked acceleration of lung development with a precocious microvascular maturation resulting in single capillary network septa in the first 4 postnatal days. By postnatal d 10, the lung morphologic phenotype showed a step back in the maturational state, with an increased number of septa with double capillary layer, followed by an exceptional second round of the alveolarization process. As a result of this process, there was an almost complete recovery in the parenchymal lung structure by postnatal d 36, and by d 60, there were virtually no qualitative or quantitative differences between experimental and control rats. These findings indicate that both dosage and duration of glucocorticoid therapy in the early postnatal period are very critical with respect to lung development and maturation and that a careful therapeutic strategy can minimize late sequelae of treatment.     

Effects of mild vitamin a deficiency on lung maturation in newborn rats: a morphometric and morphologic study

OBJECTIVE: To evaluate the effects of a 60% vitamin A deficiency (VAD) on the two postnatal stages of lung development: alveolarization and microvascular maturation. Lungs from deficient rats were compared to age-matched controls. STUDY DESIGN: Starting at 3 weeks before mating, female rats were maintained under a diet lacking vitamin A. Due to the slow depletion of the vitamin A liver stores the pregnant rats carried to term and delivered pups under mild VAD conditions. Mothers and offspring were then kept under the same diet what resulted in a mean reduction of vitamin A plasma concentration of about 60% vs. controls during the whole experimental period. Pups were sacrificed on days 4, 10 and 21 and their lungs fixed and analyzed by means of a combined morphologic and morphometric investigation at light and electron microscopic levels. RESULTS: During the whole experiment, body weights of VAD animals were lower than controls with a significant decrease on day 10. On days 4, 10 and 21 the pulmonary structure was in a comparable gross morphologic state in both groups. Despite this morphologic normality, quantitative alterations in some functional parameters could be detected. On day 4, lung volume and the volume and surface area of air spaces were decreased, while the arithmetic mean barrier thickness and type 2 pneumocyte volume were increased in the VAD group. On day 21, some changes were again manifest mainly consisting in an augmentation of the vascularization and a decrease in interstitial volume in deficient animals. CONCLUSIONS: Mild VAD causes no gross disturbances in the postnatal phases of lung development in rats. However, a body weight-related transient retardation of lung maturation was detectable in the first postnatal week. At 3 weeks, the VAD lungs showed a more mature vascular system substantiated by an increase in volume of both capillary volume and the large non-parenchymal vessels. In view of these quantitative alterations, we suspect that mild VAD deregulates the normal phases of body and lung growth, but does not induce serious functional impairments.     

Structural maturation of the human fetal lung: a morphometric study of the development of air-blood barriers

To quantitatively follow the progressive capillarization of the fetal airway epithelium, we examined human lung tissue from nine fetuses ranging in gestational age from 18-26 wk. Our goals were to 1) determine the initial time of appearance of the air blood barrier (ABB) in the fetus; 2) follow the increase in the number of ABB per total epithelial airway surface (capillary load) with gestational age; and 3) measure the thickness of the ABB. Our results, obtained by using light and electron microscopy and an interactive computerized morphometry system, show that ABB first appear at 19 wk. Increasing gestation is accompanied by an exponential increase in the number of ABB (r = 0.96) and the total surface area that the ABB contribute to the total surface area of airway epithelium (r = 0.93). ABB thickness is comparable to the dimensions of minimal barrier thickness of the adult ABB. The structural development that we describe may be one of the factors determining preterm viability.     

Biochemical maturation of fetal rat lung: a comprehensive study including surfactant determination

The paper describes a comprehensive assessment of lung growth and biochemical maturation in the fetal and early postnatal rat. Fetal lung grew faster than whole body between gestational day 16.5 and term. Cell number increased quasi-exponentially, except for a slowing of cell growth between days 19.5 and 20.5 of gestation. By contrast, growth was limited during the two first postnatal days. Percentage of dry tissue and protein concentration increased in parallel during the whole period. Increases in whole lung tissue phosphatidylcholine were greatest between 20.5 and 21.5 days of gestation, whereas in isolated surfactant fraction, changes were most marked between 19.5 and 20.5 days. The most striking changes were a 19-fold increase in phosphatidylcholine and a 12.5-fold increase in the total phospholipid concentrations in the surfactant fraction between gestational day 19.5 and 1 day postpartum. Similar changes occurred in disaturated phosphatidylcholine (DSPC) concentration. During the same period, phospholipids of the residual (nonsurfactant) fraction increased only about 2-fold. These data indicate that analysis of an isolated surfactant fraction is advantageous in providing a very sensitive index of augmented phospholipid production during the process of fetal lung maturation. Evidence of biochemical maturation was detected earlier in females than in males, as indicated by a significantly larger surfactant fraction DSPC concentration in 19.5-day-old females; however, this difference was modest in degree and very transient, since it was no longer demonstrable in later stages.     

Prenatal management of the fetus with lethal malformation: from a study of oligohydramnios sequence

47 cases of oligohydramnios sequence (OS) diagnosed at Kanagawa Children's Medical Center from 1992 to 2008 were studied retrospectively. Early termination of pregnancy was chosen in 9 cases, observed natural labor was chosen in 23 cases, and 18 cases resulted in natural deliveries. Fetal demise occurred during labor in 44.4% of terminated cases, while it occurred in 5.6% of observed cases. Preterm labors and breech presentations occurred most frequently. Most infants died within 18 hours after their births. There were 3 familial cases. These results provide important information for planning the perinatal care when fetuses are diagnosed with OS.     

Transfusion-related acute lung injury treated with surfactant in a neonate

A term, male neonate suddenly developed respiratory distress and severe cyanosis while undergoing exchange transfusion for hyperbilribinaemia. Transfusion-related acute lung injury was diagnosed. Because of persistent hypoxaemia despite aggressive treatment, two doses of surfactant were administered, resulting in marked improvement.     

A morphometric study of lung maturation in the adrenocorticotrophin-infused fetal lamb.

Adrenocorticotrophin (ACTH) effects on lung development were studied in sheep. ACTH was infused into 10 fetal lambs at 129 days of gestation at a rate of 29, 110 or 250 micrograms/day for 72 h, a time course which was independent of the mechanical and hormonal forces associated with labor. Lungs were compared with those of normal fetuses at term (day 147). ACTH accelerates maturation of components of lung structure toward term values. Different components of cytodifferentiation of the type II alveolar cell showed different levels of sensitivity. The degree of acceleration, not the nature of the changes, was influenced by dose.     

Effect of maternal dexamethasone treatment on the type II pneumocytes in hypoplastic lung by oligohydramnios: an ultrastructural study

A previous study documented the effects of maternal corticosteroid treatment on structural growth and functional development in fetal lungs associated with pathogenic conditions such as oligohydramnios using immunohistochemical and morphometric analyses. The purpose of the present study was to examine the effect of maternal dexamethasone treatment the expression of lamellar body in type II pneumocytes of the fetal rabbit lungs with hypoplasia induced by oligohydramnios using electron microscopy. Using an amniotic shunting rabbit model, pregnant rabbits were injected intravenously with either 0.1 ml of saline or 0.25 mg/kg/day of dexamethasone in 0.1 ml of saline 48 and 24 h before the delivery of fetuses, at day 30 of gestation. The number of lamellar bodies per type II pneumocyte was counted in each group using electron micrographs. The number of lamellar bodies per type II pneumocyte in the lungs of the shunted group that received saline was consistently and significantly less than that of the other three groups (5.49 ± 2.07 vs. 7.34 ± 2.27: shunted group that received dexamethasone, 7.58 ± 2.08: non-shunted group that received saline, 7.79 ± 1.90: non-shunted group that received dexamethasone; P < 0.01). These results suggest that maternal dexamethasone treatment accelerates the maturation of the surfactant system, especially the expression of lamellar bodies in type II pneumocytes, even in hypoplastic lungs induced by oligohydramnios.     

Hepatic erythropoiesis in infants of diabetic mothers: a morphometric study

Hepatic erythropoietic tissue is inversely proportional to the gestational age both in infants of diabetic mothers and in control cases. Hepatic erythropoietic and indices range from 17.8 in fetuses and babies before 28 weeks' gestational age to about 1.0 in fetuses and babies at 40-42 weeks' gestational age. The decline with gestational age is gradual in the last 10-12 weeks of in utero development. Infants of diabetic mothers who are normally grown have normal amounts of erythropoiesis in their livers. At term, large infants of diabetic mothers have excessive hepatic erythropoiesis. Hypoxia, a frequent feature in infants of diabetic mothers, is probably responsible for the increased erythropoiesis, but an alternate mechanism may be that hyperinsulinemia directly stimulates erythroid precursors or erythropoietin production.     

Nitric oxide inhalation therapy in very low-birthweight infants with hypoplastic lung due to oligohydramnios

BACKGROUND: Although nitric oxide inhalation (iNO) therapy improves arterial oxygenation and reduces the rate of extracorporeal membrane oxygenation in term neonates, the efficacy of this therapy in premature infants is controversial. The objective of the present study was to determine whether iNO therapy improves the survival of very low-birthweight infants with pulmonary hypoplasia due to prolonged rupture of membrane. METHODS: A retrospective comparative study of very low-birthweight infants with pulmonary hypoplasia due to oligohydramnios who had or had not been treated with iNO therapy, was performed (iNO-treated group, eight infants; control group, 10 infants). A neonate was considered to have pulmonary hypoplasia due to oligohydramnios if the following conditions were satisfied: (i) artificial surfactant treatment did not improve the respiratory distress; (ii) prolonged rupture of membrane (PROM) continued for more than 5 days with oligohydramnios; and (iii) sufficient arterial oxygenation did not occur even after giving 100% oxygen, and more than 8 cm H(2)O of mean airway pressure was needed to maintain arterial oxygenation. RESULTS: Nitric oxide inhalation improved arterial oxygenation rapidly and consistently in all eight infants with pulmonary hypoplasia. All eight iNO-treated infants survived longer than 28 days, while five of the 10 control infants died within 24 h of birth (P < 0.05). Before starting iNO, seven of the eight treated infants had shown persistent pulmonary hypertension, which was confirmed by echocardiography. No iNO-treated infant had IVH greater than grade 1, while one control infant had grade 2 IVH. All six long-term survivors in the iNO-treated group are developing normally, while only two of the control infants are developing normally as of February 2002. CONCLUSIONS: The majority of the infants with pulmonary hypoplasia due to oligohydramnios had persistent pulmonary hypertension. iNO improved the arterial oxygenation and significantly improved the survival rate. A controlled study to determine whether iNO therapy improves the survival rate of preterm infants with pulmonary hypoplasia due to oligohydramnios is necessary.     

Glucocorticoid metabolism in the human fetal lung: implications for lung development and the pulmonary surfactant system

It has been nearly 35 years since Liggins and Howie first reported the benefits of antenatal glucocorticoid (GC) treatment to promote the maturation of the human fetal lung, and nearly that long since Pasqualini and colleagues demonstrated that the human fetal lung actively metabolizes GCs. Since that time, our understanding of the effects of GCs on fetal lung maturation and pulmonary surfactant production has increased dramatically. Similarly, characterization of the enzymes involved in GC metabolism has greatly expanded our understanding of GC signaling in target tissues. In man, the biologically active GC (cortisol) and the biologically inactive GC (cortisone) are interconverted by the tissue-specific expression of the type 1 and type 2 11beta-hydroxysteroid dehydrogenase enzymes (HSD1 and HSD2). Much of the research on GC metabolism in peripheral target tissues has focused on the role of HSD1 in amplifying the effects of GCs in liver and adipose tissue or on the role of HSD2 in blocking the effects of GCs in the kidney and placenta. In contrast, the role of GC metabolism in modulating the effects of GCs on fetal lung maturation and the pulmonary surfactant system in humans is less understood. The goal of this review article is to present a brief overview of the role of GCs in human fetal lung maturation and pulmonary surfactant production, and to familiarize the reader with the biochemistry of the metabolism of natural and synthetic GCs by the HSD enzymes. In addition, we will review data concerning the expression and activity of the HSD enzymes in the human fetal lung and contrast this to what is known about the HSD enzymes in the fetal rodent lung. Although rodents, rabbits, sheep, and several primates have been invaluable model systems for the study of fetal lung development, we have chosen to largely focus this review on human lung, since there are significant differences in GC metabolism between humans and other species.     

Undernutrition in Nepalese children: a biochemical and haematological study

Aim: This study was undertaken to assess the nutritional status of 6–10 years old Nepalese children by measuring some haematological and biochemical parameters. Methods: Nutritional status was assessed by height‐for‐age z‐score. Total count of red blood corpuscles (TC of RBC), packed cell volume, haemoglobin concentration, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration were measured. Biochemical parameters such as serum iron, total iron‐binding capacity (TIBC), serum ferritin, serum transferrin, transferrin saturation (TS) and serum albumin were also measured. Serum folate and vitamin B₁₂ were measured in well‐nourished and undernourished children. Results: TC of RBC, serum iron, serum ferritin, TS and serum albumin of stunted children were significantly lower (p < 0.05) than that of well‐nourished children. MCV, MCH, TIBC and serum transferrin of stunted children were significantly higher (p < 0.05) than that of well‐nourished children. Serum folate and vitamin B₁₂ values of stunted children were significantly lower (p < 0.001) than that of well‐nourished children. Conclusion: A mild iron deficiency was found in stunted Nepalese children. The serum ferritin has been identified as a sensitive marker for measurement of iron status in surveyed children. A deficiency of serum protein, serum folate and vitamin B₁₂ was also found in the undernourished Nepalese children.     

Serum plasminogen and lung surfactant in the respiratory distress syndrome

Plasminogen, total protein, and surface-active material were measured in amniotic fluid in 112 pregnancies at 11-42 weeks' gestation. In 65 of these pregnancies, cord blood was also analyzed for serum plasminogen and total protein. Plasminogen was detected in 25 of 114 amniotic fluid samples, and 23 came from pregnancies of less than 37 weeks' gestation. Plasminogen was found in 15 of 32 amniotic fluid samples from pregnancies with complications, but only in 10 of 80 "uncomplicated" pregnancies. The mean cord serum plasminogen was relatively constant in births or abortuses of 17 to 30 weeks' gestation, but was present in increasing amounts in births of gestational ages from 30 to 40 weeks. The concentration of plasminogen in cord serum was directly related to the cord total protein (r = 0.7513, P less than 0.001). The cord plasminogen concentration was significantly higher in infants with a positive foam stability test (5.6 +/- 0.3 mg/100 ml) than in the combined group of infants with negative and intermediate tests (4.3 +/- 0.16, P less than 0.005). However, infants with a positive foam stability also had a significantly greater gestational age than infants with a negative or intermediate foam stability test. With one exception, infants with a low cord plasminogen (below 4 mg/100 ml) developed respiratory distress syndrome (RDS) only if amniotic fluid surfactant was low. The data suggest that low levels of serum plasminogen are correlated with severe lung disease only in the presence of surfactant deficiency.     

Effect of exogenous surfactant on the development of surfactant synthesis in premature rabbit lung

Surfactant replacement is an effective therapy for neonatal respiratory distress syndrome. Full recovery from respiratory distress syndrome requires development of endogenous surfactant synthesis and metabolism. The influence of exogenous surfactant on the development of surfactant synthesis in premature lungs is not known. We hypothesized that different exogenous surfactants have different effects on the development of endogenous surfactant production in the premature lung. We treated organ cultures of d 25 fetal rabbit lung for 3 d with 100 mg/kg body weight of natural rabbit surfactant, Survanta, and Exosurf and measured their effects on the development of surfactant synthesis. Additional experiments tested how these surfactants and Curosurf affected surfactant protein (SP) SP-A, SP-B, and SP-C mRNA expression. Surfactant synthesis was measured as the incorporation of 3H-choline and 14C-glycerol into disaturated phosphatidylcholine recovered from lamellar bodies. Randomized-block ANOVA showed significant differences among treatments for incorporation of both labels (p < 0.01), with natural rabbit surfactant less than control, Survanta greater than control, and Exosurf unchanged. Additional experiments with natural rabbit surfactant alone showed no significant effects in doses up to 1000 mg/kg. Survanta stimulated disaturated phosphatidylcholine synthesis (173 +/- 41% of control; p = 0.01), increased total lamellar body disaturated phosphatidylcholine by 22% (p < 0.05), and increased 14C-disat-PC specific activity by 35% (p < 0.05). The response to Survanta was dose-dependent up to 1000 mg/kg. Survanta did not affect surfactant release. No surfactant altered the expression of mRNA for SP-A, SP-B, or SP-C. We conclude that surfactant replacement therapy can enhance the maturation of surfactant synthesis, but this potential benefit differs with different surfactant preparations.