摘要:

Fibroblast growth factors (FGF) are known to have key roles in embryonic growth and morphogenesis, but their presence and contributions to fetal development are unclear. In particular, little information exists as to the relevance of FGF and their specific receptors to human fetal development. We studied the anatomical distribution of messenger RNA encoding FGF-2 and one of its high affinity receptors, FGFR1, usingin situhybridization in a variety of human fetal tissues in early second trimester. Corresponding protein distributions were determined by immunohistochemistry. Both FGF-2 and FGFR1 mRNA and proteins were found to be present in every organ and tissue examined, but with defined cellular localizations. In skeletal muscle, both FGF-2 and FGFR1 mRNA and peptides were present in differentiated fibers, and both co-localized to proliferating chondrocytes of the epiphyseal growth plate. FGF-2 and FGFR1 mRNA and peptides were also present within cardiac or gastrointestinal smooth muscle. Within the gastrointestinal tract FGF-2 mRNA and peptide were located in the submucosal tissue, whereas FGFR1 was expressed within the overlying mucosa. Similarly, in skin, FGF-2 was expressed within the dermis whereas FGFR1 mRNA and peptide were most apparent in the stratum germinativum of the epidermis. In kidney and lung, FGFR1 mRNA was located in the tubular and alveolar epithelia respectively, whereas FGF-2 was expressed in both epithelial and mesenchymal cell populations. Both growth factor and receptor were widespread in both neuroblasts and glioblasts in the cerebral cortex of the brain. Immunoreactivity for FGF-2 and FGFR1 was seen in all vascular endothelial cells of major vessels and capillaries. Within the skin, kidney, lung, and intestine FGF-2 immunoreactivity was found in basement membranes underlying epithelia, and was associated with the extracellular matrix and plasma membranes of many cell types. The results show that FGF-2 and one of its receptors are widely expressed anatomically in the mid-trimester human fetus.Abbreviations: FGF,fibroblast growth factor;FGFR,fibroblast growth factor receptor

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Hepatocyte growth factor (HGF) is expressed in placental syncitium and fetal organs and acts as a mitogen, motogen, and morphogenin vitro, suggesting a role in fetal growth and development. We aimed to examine the correlates of serum HGF in human cord blood. HGF was measured by ELISA using recombinant human HGF and mouse MAb to recombinant human HGF (Immunology Institute, Tokyo). Umbilical vein blood was collected prospectively at 148 deliveries including 94 normal pregnancies and 54 pregnancies complicated by medical conditions, primarily diabetes mellitus and pregnancy-induced hypertension. Growth parameters, gestation, pregnancy history, and perinatal events were recorded. Sera from 54 adolescents and 32 adult controls were also analyzed. Cord HGF [0.97 (0.66-1.33) ng/mL] [median (25-75 percentile)] was higher than HGF levels in adolescent sera [0.28 (0.21-0.35) ng/mL,p< 0.0001] and adult control sera [0.23 (0.14-0.31) ng/mL,p< 0.0001]. Cord HGF correlated with gestational age (r= 0.42,p= 0.0001) in normal pregnancies, with term babies (n= 69) having higher cord HGF than babies less than 37 wk of gestation(n= 25) [1.11 (0.78-1.45), 0.78 (0.46-1.03) ng/mL,p= 0.0007]. However, there was no relationship between gestation and cord HGF in complicated pregnancies. Cord HGF did not differ at term between appropriate for gestational age babies and small for gestational age babies. There were no independent correlations between cord HGF and birth weight, birth length and placental weight. We provide evidence for the first time that cord HGF levels are high and relate to gestation in normal pregnancies. HGF may have a significant role in fetal development during pregnancy.Abbreviations: HGF,hepatocyte growth factor;TGF,transforming growth factor;NGF,nerve growth factor;rh,recombinant human

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Intrauterine growth retardation (IUGR) resulting from placental insufficiency is a common complication of pregnancy. Bilateral uterine artery ligation of the pregnant rat is a model which mimics intrauterine growth retardation in the human. IUGR rat fetuses have altered hepatic energy and redox states, with reduced fetal hepatic ATP/ADP ratio, increased cytosolic NAD+/NADH ratio, and decreased mitochondrial NAD+/NADH ratio. These critical changes in energy metabolism contribute to IUGR. The effects of these changes at the molecular level are largely unknown. To address these effects we compared hepatic mRNA populations of IUGR and normal fetuses and neonates using mRNA differential display, a polymerase chain reaction-based method for assaying transcriptional differences under various conditions. We isolated and sequenced 18 cDNA products whose mRNA levels were elevated in IUGR compared with normal fetal and neonatal liver. These analyses demonstrated that NADH-ubiquinone oxireductase subunit 4L mRNA (ND-4L) was significantly increased in liver of IUGR fetuses and neonates. This suggested that IUGR may be associated with altered expression of genes involved in the generation of ATP and NADH. Therefore, we measured mRNA levels of adeninenucleotide translocator-2 (ANT-2), glucose-6-phosphate dehydrogenase(G6PD), mitochondrial malate dehydrogenase (MMD), ornithine transcarbamylase(OTC), and phosphofructokinase-2 (PFK-2) using a semiquantitative reverse transcriptase-polymerase chain reaction-based technique. In the IUGR fetus, ND-4L, ANT-2, G6PD, and MMD mRNA levels were significantly elevated; PFK-2 mRNA levels were unchanged, and OTC levels were decreased. In the IUGR newborn rat, mRNA levels of all 6 enzymes were increased suggesting that the metabolic state of the growth retarded newborn remains abnormal after birth. Uteroplacental insufficiency affects the immediate and long-term metabolic milieu of the growth retarded animal, and forces specific adjustments, including the expression of mRNA encoding enzymes involved with hepatic energy production.Abbreviations: RT,reverse transcriptase;PCR,polymerase chain reaction;IUGR,intrauterine growth retardation;ND-4L,NADH-ubiquinone oxireductase subunit 4L;ANT-2,adenine-nucleotide translocator-2;G6PD,glucose-6-phosphate dehydrogenase;MMD,mitochondrial malate dehydrogenase;OTC,ornithine transcarbamylase;PFK-2,phosphofructokinase-2

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Glucocorticoids are associated with reduced weight gain when used to improve pulmonary function in premature infants. However, tissue maturation is stimulated during normal development by an increase in serum glucocorticoids. We evaluated the effects of glucocorticoid treatment on tissue weight gain and the activity of specific enzymes in the suckling rat, with the hypothesis that these processes are independently regulated. Before the ontogenic surge in corticosterone, 6-d-old rat pups were implanted with a pellet to release corticosterone continuously at 0 (placebo), 48, 120, 240, or 360 μg/d. We killed the pups at 7, 9, or 12 d of age and measured tissue weights and activities of sucrase and glutamine synthetase. Serum corticosterone concentrations were elevated with dose. Tissue weight gain was proportional to lneserum corticosterone at all ages. In contrast, enzyme indices of tissue maturation did not respond to corticosterone until d 9. Also, intestinal tissue was more sensitive than muscle to the effects of corticosterone on weight but less sensitive to its effects on maturation. We conclude that the immediate response, in terms of weightversusthe delayed response of the enzymes and their reciprocal sensitivity in muscle and gut, indicates that these processes are independently regulated.

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

To explore the changes in resting energy expenditure (REE) and whole body protein turnover induced by malaria, 23 children aged 6 to 14 y (23.9 ± 1.0 kg, 1.3 ± 0.02 m) were studied on three separate days after treatment (d 1, d 2, and 15 d later). REE was assessed by indirect calorimetry(hood), whereas whole body protein turnover was estimated using a single dose of [15N]glycine administered p.o. by measuring the isotopic enrichment of [15N]ammonia in urine over 12 h. Within the first 3.5 h after treatment, the body temperature dropped from 39.8 ± 0.1 to 37.8± 0.1°C (p< 0.0001), and REE followed the same pattern, decreasing rapidly from 223 ± 6 to 187 ± 4 kJ/kg/d(p< 0.0001). Whole body protein synthesis and breakdown were significantly higher during the 1st day (5.65 ± 0.38 and 6.21 ± 0.43 g/kg/d, respectively) than at d 15 (2.95 ± 0.17 and 2.77 ± 0.2 g/kg/d). It is concluded that Gambian children suffering from an acute episode of malaria have an increased REE averaging 37% of the control value (d 15) and that this was associated with a substantial increase (by a factor of 2) in whole body protein turnover. A rapid normalization of the hypermetabolism and protein hypercatabolism states after treatment was observed.Abbreviations: REE,resting energy expenditure;HR,heart rate

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

To clarify the influence of nutrition on the GH-IGF axis in protein-energy malnutrition (PEM), we determined the serum levels of GH, GH-binding proteins(BP) (GHBPs), IGF-I, and IGFBPs in nine children with kwashiorkor and 13 with marasmus, before and after nutritional rehabilitation. In a basal condition, the GH level was significantly higher in the two malnourished groups than in controls (p< 0.01); in contrast, the second fraction of GHBP was lower and seemed to be related to the high GH and to a reduction in GH receptors. After refeeding, the GH level increased and the second fraction of GHBP decreased. The IGF-I basal level was higher in kwashiorkor than in marasmus subjects (p< 0.05), but in both groups it was significantly lower than in controls (p< 0.01); after refeeding it increased. IGFBP-3, measured by RIA and Western blotting techniques, was in the control range in the kwashiorkor group but in the marasmic group it was significantly lower than in controls; after refeeding it decreased in kwashiorkor (p< 0.01versusbasal values) and increased in marasmus (p< 0.05versusprerefeeding level). When sera of malnourished patients were mixed with adult control sera, incubated for 5 h at 37°C, and assessed by ligand blotting, a low IGFBP-3 level in marasmus was found to be due to increased adaptive proteolysis of IGFBP-3; in contrast, in kwashiorkor the IGFBP-3 proteolytic activity was very low, probably because of inhibition by aflatoxins. These findings confirm that malnutrition affects the GH-IGF axis.Abbreviations: BP,binding protein;PEM,protein-energy malnutrition;AU,absorption unit

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The gastrointestinal (GI) barrier function is immature in the preterm neonate and might thus facilitate translocation of enteric bacteria and gut-derived septicemia. Circumstantial evidence suggests that bacterial uptake from the intestine may be further enhanced by an alteration of the host nutritional status. To test this hypothesis, neonatal rats were fed normal or restricted amounts of either breast milk or of a rat milk-simulated formula for 3-5 d. At the end of the study, various sections of the GI tract, mesenteric lymph nodes, liver, spleen, and blood were analyzed for bacteria using standard microbiologic procedures. Normal breast feeding was associated with bacterial translocation to mesenteric lymph nodes and in some cases to liver or spleen in 27% of rats, whereas all bacterial cultures were negative in a control group killed immediately after birth. Restricted breast feeding did not increase translocation compared with normal breast feeding. By contrast, feeding normal or restricted amounts of formula increased the numbers of gut bacteria by 2-3 logs, altered the morphology of the small intestinal mucosa, and resulted in ample bacterial translocation to the mesenteric lymph nodes and to systemic organs including the blood. Bacterial translocation may normally occur in suckling neonatal rats and is not increased by food restriction. Artificial feeding dramatically enhances translocation of gut bacteria.Abbreviation: GI,gastrointestinal

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Corticosteroids such as dexamethasone (DEX) increase leucine turnover and oxidation in humans and animals, indicating whole body protein catabolism. Recently, interest has been growing in the use of recombinant polypeptides such as GH and IGF-I in reversing various states of catabolism. The aim of our study was to investigate whether IGF-I reverses corticosteroid-induced protein catabolism in rapidly growing piglets. Also, we wanted to determine whether IGF-I attenuates corticosteroid-induced hyperglycemia. To study these questions, we performed leucine kinetic studies and measured blood glucose in eight piglets under postabsorptive conditions. We did three studies in each piglet: baseline, DEX treatment (5 mg/kg/d for 4 d), and DEX plus IGF-I treatment (25 μg/kg/h for 6 h). DEX increased leucine turnover by 18± 14% (mean ± SD,p< 0.05), and oxidation by 132± 64% (p< 0.01) over baseline values. Adding IGF-I to DEX treatment failed to reverse these changes in leucine kinetics. Turnover again increased by 18 ± 8% (p< 0.01), and oxidation by 107± 68% (p< 0.05) over baseline values. Nonoxidative leucine disposal, an indicator for protein synthesis, did not significantly differ after treatment with DEX or with DEX. plus IGF-I. Blood glucose values increased over baseline values after DEX treatment, and approached baseline values after DEX plus IGF-I. We conclude that IGF-I attenuates corticosteroid-induced hyperglycemia, but does not reverse corticosteroid-induced protein catabolism in growing piglets.Abbreviations: DEX,dexamethasone;KIC,2-ketoisocaproate;MPE,mol% excess

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

In full-term newborns, permanent closure of the ductus arteriosus is associated with the formation of a neointima that is characterized by extracellular matrix deposition and smooth muscle cell migration. Transforming growth factor-β (TGF-β), a potent modulator of extracellular matrix deposition and smooth muscle cell migration, has been found to play a role in the remodeling associated with several forms of vascular disease. We examined the protein and mRNA expression of the three mammalian isoforms of TGF-β(TGF-β1, TGF-β2, and TGF-β3) during ductus arteriosus closure in full-term lambs. We found that the temporal changes and cellular localization of the proteins and mRNAs of all three TGF-β isoforms were similar. TGF-β proteins and mRNAs were present in very low levels in the late-gestation fetal ductus. Within 24 h of delivery, there was enhanced expression of TGF-β in the newly forming neointima and outer muscle media; this continued to increase over the next 10 d. Increased expression of TGF-β in the inner muscle media and adventitia lagged behind that of the neointima and outer muscle media. TGF-β was not found in the luminal endothelial cells at any time. In contrast to the pattern described above, the appearance of TGF-β protein differed from that of mRNA in the vasa vasorum of the ductus wall. After delivery, there was an increase in TGF-β immunoreactivity in the smooth muscle cell layers of the vasa vasorum without any concurrent mRNA expression. The appearance of TGF-β at the time of ductus closure suggests an important role for this growth factor in the reorganization of the ductus wall after birth.Abbreviations: cDNA,complimentary DNA;ECM,extracellular matrix;PDGF,platelet-derived growth factor;SMC,smooth muscle cell;SSC,sodium chloride, sodium citrate;TGF-β,transforming growth factor-β

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Although endothelin (ET) contributes to the regulation of pulmonary vascular tone in the normal fetus, little is known about its role in pulmonary hypertension in the perinatal period. To examine the role of the ETBreceptor in the normal ovine fetal lung, we studied the hemodynamic effects of ET-3 (a selective ETBreceptor agonist) before and after RES-701 (a selective ETBreceptor antagonist). RES-701 (10 μg/min for 10 min) did not change basal pulmonary tone and blocked pulmonary vasodilation to ET-3(500 ng/min for 10 min). To examine the effects of experimental perinatal pulmonary hypertension on activity of the ETAand ETBreceptors, we studied the hemodynamic effects of ET-3, ET-1 (a nonselective ETAand ETBreceptor agonist), and BQ 123 (a selective ETAreceptor antagonist) in 12 chronically prepared late gestation fetal lambs after partial ligation of the ductus arteriosus. Serial changes in the pulmonary vascular effects of these agents were measured early (1-3 d) and late (7-10 d) after partial ductus arteriosus ligation. Left lung total pulmonary resistance in the normal late-gestation fetus was 0.62 ± 0.01 mm Hg/ml/min(n= 4). After partial ductus arteriosus ligation, total pulmonary resistance increased to 1.2 ± 0.3 (early;p< 0.05versusnormal), and progressively rose to 1.9 ± 0.2 mm Hg/ml/min (late;p< 0.05versusearly). Intrapulmonary infusion of ET-3 (500 ng/min for 10 min) increased pulmonary blood flow from 94 ± 11 to 183 ± 17 mL/min in the normal fetus, but had no effect during late pulmonary hypertension. Infusions of ET-1 (50 ng/min for 30 min) caused transient pulmonary vasodilation followed by vasoconstriction during early pulmonary hypertension. During late pulmonary hypertension, however, infusion of ET-1 caused predominantly vasoconstriction. Pulmonary vasodilation to BQ 123 (100 μg/min for 10 min) was greater during late than early pulmonary hypertension (43versus21%;p< 0.05). After 10 d of ductus arteriosus ligation, immunoreactive ET-1 content in whole lung tissue was 3-fold higher in hypertensive (n= 7) than control(n= 10) lungs (p< 0.05). We conclude that the ETBreceptor contributes little to regulation of basal vascular tone in the normal ovine fetal lung and that chronic intrauterine pulmonary hypertension causes the loss of ETB-mediated vasodilation, progressive ETA-mediated vasoconstriction, and increased lung ET-1 content. We speculate that diminished ETBreceptor-mediated vasodilation in combination with enhanced ETAreceptor-mediated vasoconstriction and increased ET-1 production contributes to high pulmonary vascular resistance in perinatal pulmonary hypertension.Abbreviations: ET,endothelin;PPHN,persistent pulmonary hypertension of the newborn;Paco2,arterial Pco2;Pao2,arterial Pco2;TPR,total pulmonary resistance in the left lung

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID