Zimmermann, L.J.I.

Increased protein-energy intake promotes anabolism in critically ill infants with viral bronchiolitis: A double-blind randomised controlled trial (Article)

2011-09-01T00:00:00Z

Objective: The preservation of nutritional status and growth is an important aim in critically ill infants, but difficult to achieve due to the metabolic stress response and inadequate nutritional intake, leading to negative protein balance. This study investigated whether increasing protein and energy intakes can promote anabolism. The primary outcome was whole body protein balance, and the secondary outcome was first pass splanchnic phenylalanine extraction (SPEPhe). Design: This was a double-blind randomised controlled trial. Infants (n=18) admitted to the paediatric intensive care unit with respiratory failure due to viral bronchiolitis were randomised to continuous enteral feeding with protein and energy enriched formula (PE-formula) (n=8; 3.1±0.3 g protein/kg/24 h, 119±25 kcal/kg/24 h) or standard formula (S-formula) (n=10; 1.7±0.2 g protein/kg/24 h, 84±15 kcal/kg/24 h; equivalent to recommended intakes for healthy infants <6 months). A combined intravenous-enteral phenylalanine stable isotope protocol was used on day 5 after admission to determine whole body protein metabolism and SPEPhe. Results: Protein balance was significantly higher with PE-formula than with S-formula (PE-formula: 0.73±0.5 vs S-formula: 0.02±0.6 g/kg/24 h) resulting from significantly increased protein synthesis (PE-formula: 9.6±4.4, S-formula: 5.2±2.3 g/kg/24 h), despite significantly increased protein breakdown (PE-formula: 8.9±4.3, S-formula: 5.2±2.6 g/kg/24 h). SPEPhewas not statistically different between the two groups (PE-formula: 39.8±18.3%, S-formula: 52.4±13.6%). Conclusions: Increasing protein and energy intakes promotes protein anabolism in critically ill infants in the first days after admission. Since this is an important target of nutritional support, increased protein and energy intakes should be preferred above standard intakes in these infants. Dutch Trial Register number: NTR 515.

Body image distortions in bulimia nervosa: Investigating body size overestimation and body size satisfaction by fMRI (Article)

2011-06-01T00:00:00Z

Background: Body image distortion is a key symptom of eating disorders. In behavioral research two components of body image have been defined: attitudes towards the body and body size estimation. Only few fMRI-studies investigated the neural correlates of body image in bulimia; those are constrained by the lack of a direct distinction between these different body image components. Methods: The present study investigates the neural correlates of two aspects of the body image using fMRI: satisfaction rating and size estimation of distorted own body photographs in bulimia nervosa patients (15) and controls (16). Results: Patients were less satisfied with their current body shape than controls and preferred to be thinner. The amount of insula activity reflects the pattern of the satisfaction rating for patients and controls.Patients also overestimated their own body size. For control subjects, an activated cluster in lateral occipital cortex was sensitive for body size distortions, whereas bulimic patients did not demonstrate such a modulation. Furthermore, bulimic subjects did not recruit the middle frontal gyrus (MFG) in contrast to controls during the body size estimation task, maybe indicating a reduced spatial manipulation capacity. Therefore, this activation pattern of lateral occipital cortex and MFG might be responsible for body size overestimation in bulimia. Conclusions: The present results show that bulimic patients exhibit two distinct deficits in body image representations similar to anorectic patients and that specifically associated neuronal correlates can be identified. Concludingly, our study support psychotherapeutic strategies specifically targeting these two aspects of body image distortions.

Chlamydia trachomatis and placental inflammation in early preterm delivery (Article)

2011-05-01T00:00:00Z

Chlamydia trachomatis may infect the placenta and subsequently lead to preterm delivery. Our aim was to evaluate the relationship between the presence of Chlamydia trachomatis and signs of placental inflammation in women who delivered at 32 weeks gestation or less. Setting: placental histology and clinical data were prospectively obtained from 304 women and newborns at the Erasmus MC-Sophia, Rotterdam, the Netherlands. C. trachomatis testing of placentas was done retrospectively using PCR. C. trachomatis was detected in 76 (25%) placentas. Histological evidence of placental inflammation was present in 123 (40%) placentas: in 41/76 (54%) placentas with C. trachomatis versus 82/228 (36%) placentas without C. trachomatis infection (OR 2.1, 95% CI 1.2-3.5). C. trachomatis infection correlated with the progression (P = 0.009) and intensity (P = 0.007) of materno-fetal placental inflammation. C. trachomatis DNA was frequently detected in the placenta of women with early preterm delivery, and was associated with histopathological signs of placental inflammation.

Reply (Letter To Editor)

2010-10-01T00:00:00Z

Chorioamnionitis Alters the Response to Surfactant in Preterm Infants (Article)

2010-01-01T00:00:00Z

Objective: To study the association between antenatal exposure to chorioamnionitis and the neonatal response to surfactant. Study design: Prospective observational cohort of 301 preterm infants of gestational age ≤ 32.0 weeks, 146 of whom received surfactant according to standardized criteria. Fraction of inspired oxygen (FiO2) requirement (using analysis of variance) and time to extubation (using Kaplan-Meier and Cox regression analyses) were compared between groups based on the presence of histological chorioamnionitis (HC) with or without fetal involvement (HC-, n = 88; HC + F-, n = 25; HC + F+, n = 33) and between infants who developed bronchopulmonary dysplasia (BPD) or died (n = 57) and BPD-free survivors (n = 89). Multiple logistic regression was performed to investigate the association between HC and BPD. Results: Compared with HC- infants, HC + F+ infants had significantly greater FiO2requirement and prolonged time to extubation postsurfactant, not accounted for by differences in gestational age and birth weight. Infants with BPD/death had a strikingly similar pattern of increased FiO2requirement postsurfactant. Moreover, in infants who received surfactant, HC + F+ status was associated with increased risk for BPD (odds ratio [OR] = 3.40; 95% confidence interval [CI] = 1.02-11.3; P = .047) and for BPD/death (OR = 2.72; 95% CI = 1.00-7.42; P = .049). Conclusions: An impaired surfactant response was observed in preterm infants with severe chorioamnionitis and may be involved in the association between chorioamnionitis, mechanical ventilation, and the development of BPD.

Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants (Article)

2009-12-01T00:00:00Z

Objective: The objective of the study was to study the effects of histologic chorioamnionitis (HC) with or without fetal involvement and antenatal steroid (AS) exposure on neonatal outcome in a prospective cohort of preterm infants. Study Design: The clinical characteristics and placental histology were prospectively collected in 301 infants born at a gestational age 32.0 weeks or less in the Erasmus University Medical Center. Results: In univariable analyses, HC without fetal involvement (n = 53) was associated with decreased severe respiratory distress syndrome (RDS) (11% vs 28%; P < .05), whereas HC with fetal involvement infants (n = 68) had more necrotizing enterocolitis (9% vs 2%; P < .05), intraventricular hemorrhage (IVH) (25% vs 12%; P < .05), and neonatal mortality (19% vs 9%; P < .05). In HC without fetal involvement infants, AS reduced the incidences of RDS (43% vs 85%; P < .05) and IVH (5% vs 39%; P < .01). In multivariable analyses, HC without fetal involvement was associated with decreased severe RDS (odds ratio, 0.22; 95% confidence interval, 0.05-0.93; P < .05) and increased early-onset sepsis (odds ratio, 2.22; 95% confidence interval, 1.02-4.83; P < .05). Conclusion: In a prospective cohort of preterm infants, multivariable analyses reveal only a modest association between histologic chorioamnionitis and neonatal outcome.

Early postnatal blood pressure in preterm infants: Effects of chorioamnionitis and timing of antenatal steroids (Article)

2009-11-01T00:00:00Z

Previous studies suggest postnatal blood pressure in preterm infants to be decreased by chorioamnionitis and increased by antenatal steroids (AS). We examined the adjusted effects of both antenatal modulators on postnatal blood pressure (BP), with separate effects reported for histologic chorioamnionitis with or without fetal involvement and timing of AS. General characteristics, BP, and heart rate values during the first 72 h after birth were obtained from 271 infants with gestational, age ≤32.0 wk. In unadjusted analyses, chorioamnionitis was associated with lower BP, most prominently so in infants with fetal involvement, without an effect on hypotension incidence. AS increased BP and decreased the incidence of hypotension when administered within 7 d before birth. In a multivariable mixed model analysis, the AS effect remained significant, whereas chorioamnionitis was not independently predictive of postnatal BP. Other variables associated with increased postnatal BP were gestational age and umbilical artery pH, whereas hemolysis, elevated liver enzymes, low platelets syndrome was associated with decreased BP. In conclusion, AS seem to increase postnatal BP and decrease hypotension in preterm infants when given within 7 d before birth. Conversely, chorioamnionitis did not significantly affect postnatal BP after multivariable adjustment. Copyright

Decreased surfactant phosphatidylcholine synthesis in neonates with congenital diaphragmatic hernia during extracorporeal membrane oxygenation (Article)

2009-10-01T00:00:00Z

Purpose: Congenital diaphragmatic hernia (CDH) may result in severe respiratory insufficiency with a high morbidity. The role of a disturbed surfactant metabolism in the pathogenesis of CDH is unclear. We therefore studied endogenous surfactant metabolism in the most severe CDH patients who required extracorporeal membrane oxygenation (ECMO). Methods: Eleven neonates with CDH who required ECMO and ten ventilated neonates without significant lung disease received a 24-h infusion of the stable isotope [U-13C] glucose. The13C-incorporation into palmitic acid in surfactant phosphatidylcholine (PC) isolated from serial tracheal aspirates was measured. Mean PC concentration in epithelial lining fluid (ELF) was measured during the first 4 days of the study. Results: Fractional surfactant PC synthesis was decreased in CDH-ECMO patients compared to controls (2.4 ± 0.33 vs. 8.0 ± 2.4%/day, p = 0.04). The control group had a higher maximal enrichment (0.18 ± 0.03 vs. 0.09 ± 0.02 APE, p = 0.04) and reached this maximal enrichment earlier (46.7 ± 3.0 vs. 69.4 ± 6.6 h, p = 0.004) compared to the CDH-ECMO group, which reflects higher and faster precursor incorporation in the control group. Surfactant PC concentration in ELF was similar in both groups. Conclusion: These results show that CDH patients who require ECMO have a decreased surfactant PC synthesis, which may be part of the pathogenesis of severe pulmonary insufficiency and has a negative impact on weaning from ECMO.

Critically ill infants benefit from early administration of protein and energy-enriched formula: A randomized controlled trial (Article)

2009-06-01T00:00:00Z

Background & aims: Nutritional support improves outcome in critically ill infants but is impeded by fluid restriction, gastric intolerance and feeding interruptions. Protein and energy-enriched infant formulas may help to achieve nutritional targets earlier during admission and promote anabolism. Methods: Randomized controlled design. Infants with respiratory failure due to RSV-bronchiolitis received a protein and energy-enriched formula (PE-formula, n = 8) or a standard formula (S-formula, n = 10) during 5 days after admission. Primary outcome: nutrient delivery, energy and nitrogen balance and plasma amino acid concentrations. Secondary outcome: tolerance and safety. Results: Nutrient intakes were higher in PE fed infants and met population reference intake (PRI) on day 3-5 whilst in S-fed infants PRI was met on day 5 only. Cumulative nitrogen balance (cNB) and energy balance (cEB) were higher in PE-infants compared to S-infants (cNB: 866 ± 113 vs. 296 ± 71 mg/kg; cEB: 151 ± 31 and 26 ± 17 kcal/kg, both P < 0.01). Essential amino acid levels were higher in PE-infants but within reference limits whereas below these limits in S-infants. Both formulas were well tolerated. Conclusions: Early administration of a protein and energy-enriched formula in critically ill infants is well tolerated, promotes a more adequate nutrient intake and improves energy and nitrogen balance without adverse effects.

Effect of SP-B peptides on the uptake of liposomes by alveolar cells (Article)

2007-06-01T00:00:00Z

Background: Exogenous surfactant has been accepted worldwide as a therapy of RDS in premature and term infants. Exogenous surfactant is usually derived from lung extracts containing phospholipids and the surfactant proteins SP-B and SP-C. Synthetic peptides of SP-B and SP-C are being tested with the aim to develop a completely synthetic surfactant preparation. Nevertheless, the effects of these peptides on the endogenous surfactant metabolism remain unknown. Objectives: The effect of synthetic SP-B peptides on uptake of surfactant-like liposomes was investigated in alveolar cells. Native SP-B and seven SP-B peptides were included: monomeric and dimeric SP-B1-25(Cys-11 → Ala-11), SP-B63-78and Ala-SP-B63-78(Cys-71 → Ala-71;Cys-77 → Ala-77)and their serine mutants. Methods: In vitro, alveolar macrophages (AM) and alveolar type II cells (ATII) were incubated with liposomes containing SP-B or one of its peptides. In vivo, rats received intratracheally various SP-B peptides (SP-B/lipid ratio 1:33 w/w) incorporated in fluorescent surfactant-like liposomes. One hour after instillation, AM and ATII were isolated and cell-associated fluorescence was determined using flow cytometry. Confocal laser microscopy was performed to ensure internalization of the liposomes. Results: In vitro uptake by AM or ATII was not influenced by the SP-B peptides. In vivo, SP-B1-25and Ser-SP-B1-25increased the uptake by AM whereas dSP-B1-25decreased the uptake. Neither SP-B1-25nor dSP-B1-25affected total uptake by ATII. The overall uptake by SP-B63-78variants was not changed. Conclusions: Surface-active synthetic SP-B peptides do not interfere with the normaluptake of surfactant by ATII. Copyright

Albumin synthesis in preterm infants on the first day of life studied with [1-13C]leucine (Article)

2007-04-01T00:00:00Z

Albumin is the major binding protein in the human neonate. Low production of albumin will lower its transport and binding capacity. This is especially important in preterm infants, in whom albumin binds to potentially toxic products such as bilirubin and antibiotics. To study the metabolism of plasma albumin in preterm infants, we administered a 24-h constant infusion of [1-13C]leucine to 24 very low birth weight (VLBW) infants (28.4 ± 0.4 wk, 1,080 ± 75 g) on the first day of life. The caloric intake consisted of glucose only, and therefore amino acids for albumin synthesis were derived from proteolysis. The fractional synthesis rate (FSR) of plasma albumin was 13.9 ± 1.5%/day, and the absolute synthesis rate was 148 ± 17 mg·kg-1·day-1. Synthesis rates were significantly lower (P < 0.03) in infants showing intrauterine growth retardation. Albumin synthesis increased with increasing SD scores for gestation and weight (P < 0.05). The FSR of albumin tended to increase by 37% after administration of antenatal corticosteroids to improve postnatal lung function (P = 0.09). We conclude that liver synthetic capacity is well developed in VLBW infants and that prenatal corticosteroids tend to increase albumin synthesis. Decreased weight gain rates in utero have effects on protein synthesis postnatally. Copyright

Influence of phosphatidylglycerol on the uptake of liposomes by alveolar cells and on lung function. (Article)

2005-05-01T00:00:00Z

The effect of phosphatidylglycerol on the uptake of surfactant-like liposomes by alveolar type II cells and alveolar macrophages as well as the effect on endogenous surfactant function was studied in vivo. Healthy ventilated rats were intratracheally instilled with fluorescent labeled liposomes with different concentrations of phosphatidylglycerol. Lung function was determined by monitoring arterial oxygenation and, at the end of the experiment, by recording static pressure-volume curves. In addition, alveolar cells were isolated, and cell-associated fluorescence was determined using flow cytometry. The results show that, in the presence of cofactors (Ca(2+), Mg(2+)), phosphatidylglycerol stimulates the uptake by alveolar macrophages but hardly affects the uptake by alveolar type II cells. High concentrations of phosphatidylglycerol reduce the number of alveolar macrophages in the alveolar space and deteriorate lung function. On the other hand, the presence of cofactors protects the lung against the negative effects of phosphatidylglycerol on endogenous surfactant and alveolar macrophages. This study indicates that the phosphatidylglycerol concentration may play a fundamental role in the surfactant function and metabolism depending on the presence of so-called cofactors like calcium and magnesium; further study is needed to clarify the mechanisms involved.

Distinct effects of SP-B and SP-C on the uptake of surfactant-like liposomes by alveolar cells in vivo and in vitro. (Article)

2004-11-01T00:00:00Z

The effects of surfactant protein B (SP-B) and SP-C on the uptake of surfactant-like liposomes by alveolar type II cells and alveolar macrophages were studied both in vivo and in vitro. In vivo, mechanically ventilated rats were intratracheally instilled with fluorescently labeled liposomes that had SP-B and/or SP-C incorporated in different concentrations. Consequently, the alveolar cells were isolated, and cell-associated fluorescence was determined using flow cytometry. The results show that the incorporation of SP-B does not influence the uptake, and it also does not in the presence of essential cofactors. The inclusion of SP-C in the liposomes enhanced the alveolar type II cells at a SP-C to lipid ratio of 2:100. If divalent cations (calcium and magnesium) were present at physiological concentrations in the liposome suspension, uptake of liposomes by alveolar macrophages was also enhanced. In vitro, the incorporation of SP-B affected uptake only at a protein-to-lipid ratio of 8:100, whereas the inclusion of SP-C in the liposomes leads to an increased uptake at a protein-to-lipid ratio of 1:100. From these results, it can be concluded that SP-B is unlikely to affect uptake of surfactant, whereas SP-C in combination with divalent cations and other solutes are capable of increasing the uptake.

A common pathway for the uptake of surfactant lipids by alveolar cells. (Article)

2004-05-01T00:00:00Z

The uptake of different surfactant lipids-dipalmitoylphosphatidylcholine (DPPC), phosphatidylglycerol (PG), or phosphatidylinositol (PI)-and liposomes with a surfactant-like composition by alveolar type II cells (alveolar type II cells) and macrophages (alveolar macrophages) was studied in vitro. Fluorescent-labeled liposomes containing either 86% of the studied lipid, i.e., DPPC, PG, PI, and 6% labeled phosphatidylethanolamine (PE) and 8% cholesterol or a lipid mixture similar to surfactant (DPPC, PG, PI, phosphatidylcholine, PE, and cholesterol in a weight ratio of 55:8:2:21:8:6) were incubated with alveolar macrophages and alveolar type II cells. The cell-associated fluorescence assessed by flow cytometry demonstrated a higher uptake of PG and PI by both alveolar macrophages and alveolar type II cells, and a lower uptake of DPPC by alveolar macrophages. In addition, fewer alveolar type II cells take up DPPC, whereas there are no differences for the alveolar macrophages in the number of cells involved in the uptake. Competition experiments with Texas Red-labeled liposomes and either DPPC liposomes or PI liposomes labeled with Bodipy indicated that all these liposomes are internalized via the same pathway by alveolar cells. Thus, lipid composition directly influences the (re)uptake of surfactant.

Dexamethasone treatment does not inhibit fibroproliferation in chronic lung disease of prematurity (Article)

2003-01-01T00:00:00Z

Pulmonary fibrosis results from excessive fibroblast proliferation and increased collagen deposition and occurs in chronic lung disease of prematurity (CLD). Platelet-derived growth factor (PDGF)-BB is mitogenic for fibroblasts and levels are increased in fibrotic lung disorders. Systemic dexamethasone (DEX) treatment improves pulmonary function and reduces inflammation in infants with or at risk of CLD. However, the effect of DEX treatment on fibroblast activity, PDGF-BB and collagen synthesis in the lungs of CLD patients is uncertain. Bronchoalveolar lavage (BAL) fluids, obtained from 15 infants at risk of CLD before and after DEX treatment, were analysed for fibroblast mitogenicity, PDGF-BB, N-terminal propeptide of collagen type III (PIIINP) and interleukin (IL)-1beta levels and inflammatory cell numbers. After DEX treatment, the mitogenic activity of BAL fluid for fibroblasts was not reduced but increased. The change in mitogenicity correlated with a change in BAL fluid PDGF-BB levels. Furthermore, BAL fluid-induced fibroblast proliferation was blocked using an inhibitor of the PDGF receptor. DEX treatment did not influence PIIINP levels, but reduced IL-1beta levels and inflammatory cell numbers in BAL fluid. This study suggests that dexamethasone treatment does not reduce fibroblast proliferation despite apparent downregulation of inflammation. The present findings do not support the use of dexamethasone for prevention of the fibrotic response in infants at risk of chronic lung disease of prematurity.

Short course dexamethasone treatment following injury inhibits bleomycin induced fibrosis in rats (Article)

2003-01-01T00:00:00Z

BACKGROUND: Corticosteroids are routinely used in patients with pulmonary fibrosis. The timing for initiation of treatment is likely to be crucial for corticosteroids to exert an antifibrotic effect. Experimental studies in animals have examined the effect of corticosteroid treatment starting before or at the time of lung injury. However, this is not representative of the human condition as treatment only begins after disease has been established. We examined the effect of a short course corticosteroid treatment starting 3 days after bleomycin induced lung injury on the development of pulmonary fibrosis. METHODS: Bleomycin (1.5 mg/kg) was instilled intratracheally into rats to induce pulmonary fibrosis. The effect of a 3-day course of dexamethasone (0.5 mg/kg) initiated 3 days after bleomycin induced lung injury on cell proliferation and collagen deposition was examined by analysing bronchoalveolar lavage (BAL) fluid and lung tissue. RESULTS: Treating bleomycin exposed animals after injury with dexamethasone for 3 days inhibited lung collagen deposition compared with animals exposed to bleomycin without dexamethasone treatment (15.2 (2.2) mg collagen/lung v 22.5 (2.1) mg/lung; p<0.05). Dexamethasone treatment reduced pulmonary parenchymal cell proliferation in bleomycin exposed rats but did not influence BAL fluid mitogenic activity for lung fibroblasts or alter the BAL fluid levels of the fibrogenic mediators transforming growth factor-beta(1), platelet derived growth factor-AB, and thrombin. CONCLUSIONS: A 3 day course of dexamethasone treatment initiated 3 days after bleomycin induced lung injury reduces lung cell proliferation and collagen deposition by mechanisms other than through reduction of transforming growth factor-beta(1), platelet derived growth factor-AB, and thrombin levels in BAL fluid. We propose that an early short course treatment with dexamethasone may be useful in inhibiting pulmonary fibrosis.

Surfactant phosphatidylcholine half-life and pool size measurements in premature baboons developing bronchopulmonary dysplasia (Article)

2002-01-01T00:00:00Z

Because minimal information is available about surfactant metabolism in bronchopulmonary dysplasia, we measured half-lives and pool sizes of surfactant phosphatidylcholine in very preterm baboons recovering from respiratory distress syndrome and developing bronchopulmonary dysplasia, using stable isotopes, radioactive isotopes, and direct pool size measurements. Eight ventilated premature baboons received (2)H-DPPC (dipalmitoyl phosphatidylcholine) on d 5 of life, and radioactive (14)C-DPPC with a treatment dose of surfactant on d 8. After 14 d, lung pool sizes of saturated phosphatidylcholine were measured. Half-life of (2)H-DPPC (d 5) in tracheal aspirates was 28 +/- 4 h (mean +/- SEM). Half-life of radioactive DPPC (d 8) was 35 +/- 4 h. Saturated phosphatidylcholine pool size measured with stable isotopes on d 5 was 129 +/- 14 micro mol/kg, and 123 +/- 11 micro mol/kg on d 14 at autopsy. Half-lives were comparable to those obtained at d 0 and d 6 in our previous baboon studies. We conclude that surfactant metabolism does not change during the early development of bronchopulmonary dysplasia, more specifically, the metabolism of exogenous surfactant on d 8 is similar to that on the day of birth. Surfactant pool size is low at birth, increases after surfactant therapy, and is kept constant during the first 2 wk of life by endogenous surfactant synthesis. Measurements with stable isotopes are comparable to measurements with radioactive tracers and measurements at autopsy.

In vivo and in vitro uptake of surfactant lipids by alveolar type II cells and macrophages. (Article)

2002-01-01T00:00:00Z

The uptake of fluorescent-labeled liposomes (with a surfactant-like composition) by alveolar macrophages and alveolar type II cells was studied using flow cytometry, in vivo by instillation of the labeled liposomes in the trachea of ventilated rats followed by isolation of the alveolar cells and determination of the cell-associated fluorescence, and in vitro by incubation of isolated alveolar cells with the fluorescent liposomes. The results show that the uptake of liposomes by the alveolar cells is time and concentration dependent. In vivo alveolar macrophages internalize more than three times as many liposomes as alveolar type II cells, whereas in vitro, the amount of internalized liposomes by these cells is approximately the same. In vitro, practically all the cells (70-75%) internalize liposomes, whereas in vivo only 30% of the alveolar type II cells ingest liposomes vs. 70% of the alveolar macrophages. These results indicate that in vivo, only a small subpopulation of alveolar type II cells is able to internalize surfactant liposomes.

Localization and potential role of matrix metalloproteinase-1 and tissue inhibitors of metalloproteinase-1 and -2 in different phases of bronchopulmonary dysplasia (Article)

2001-01-01T00:00:00Z

Bronchopulmonary dysplasia (BPD) can evolve in prematurely born infants who require mechanical ventilation because of hyaline membrane disease (HMD). The development of BPD can be divided in an acute, a regenerative, a transitional, and a chronic phase. During these different phases, extensive remodeling of the lung parenchyma with re-epithelialization of the alveoli and formation of fibrosis occurs. Matrix metalloproteinase-1 (MMP-1) is an enzyme that is involved in re-epithelialization processes, and dysregulation of MMP-1 activity contributes to fibrosis. Localization of MMP-1 and its inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, were investigated in lung tissue obtained from infants who died during different phases of BPD development. In all studied cases (n = 50) type-II pneumocytes were found to be immunoreactive for MMP-1, TIMP-1, and TIMP-2. During the acute and regenerative phase of BPD, type-II pneumocytes re-epithelialize the injured alveoli. This may suggest that MMP-1 and its inhibitors, expressed by type-II pneumocytes, play a role in the re-epithelialization process after acute lung injury. Although MMP-1 staining intensity remained constant in type-II pneumocytes during BPD development, TIMP-1 increased during the chronic fibrotic phase. This relative elevation of TIMP-1 compared with MMP-1 is indicative for reduced collagenolytic activity by type-II pneumocytes in chronic BPD and may contribute to fibrosis. Fibrotic foci in chronic BPD contained fibroblasts immunoreactive for MMP-1 and TIMP-1 and -2. This may indicate that decreased collagen turnover by fibroblasts contributes to fibrosis in BPD development.

The effect in premature infants of prenatal corticosteroids on endogenous surfactant synthesis as measured with stable isotopes (Article)

2000-01-01T00:00:00Z

Most in vitro studies show that prenatal administration of corticosteroids stimulates the synthesis of surfactant phosphatidylcholine (PC), but studies in animals are controversial. Whether prenatal corticosteroids stimulate surfactant PC synthesis in humans has not been studied. We studied endogenous surfactant PC synthesis in relation to prenatal corticosteroid treatment in 27 preterm infants with respiratory distress syndrome. Infants received a 24-h infusion of the stable isotope [U-(13)C]glucose, starting approximately 5 h after birth. We measured (13)C-incorporation into palmitic acid in surfactant PC from serial tracheal aspirates and in plasma triglycerides and phospholipids by isotope-ratio mass spectrometry. Premature infants had received either zero (n = 11), one (n = 4), or two doses (n = 12) of prenatal betamethasone (12 mg intramuscularly). The fractional synthesis rate (FSR) of surfactant PC from glucose was 1.7 +/- 0.3%/d without corticosteroid treatment, 2.9 +/- 1.4%/d with one dose of prenatal corticosteroid, and 5.8 +/- 1.3%/d after two doses of prenatal corticosteroid. Using multiple regression analysis, we found that the FSR of surfactant PC increased by 40% (confidence interval: 7 to 82%/d, p < 0.02) per dose of corticosteroid and doubled after two doses of corticosteroid. The (13)C-enrichment of plasma triglycerides and phospholipids was not increased by corticosteroid. These data show for the first time that prenatal corticosteroid treatment stimulates surfactant synthesis in the preterm infant.

Metabolism of endogenous surfactant in premature baboons and effect of prenatal corticosteroids (Article)

1999-01-01T00:00:00Z

We studied the synthesis of surfactant and the effect of prenatal betamethasone treatment in vivo in very preterm baboons. Ten pregnant baboons were randomized to receive either betamethasone (beta) or saline (control) 48 and 24 h before preterm delivery. The newborn baboons were intubated, treated with surfactant, and ventilated for 6 d. They received a 24-h infusion with the stable isotope [U-(13)C]glucose as precursor for the synthesis of palmitic acid in surfactant phosphatidylcholine (PC). Palmitic acid in surfactant PC became enriched 27 +/- 2 h after the start of the isotope infusion and was maximally enriched at 100 +/- 4 h. The fractional synthesis rate of PC palmitate in the beta group (1.5 +/- 0.2%/d) was increased by 129% above control (0.7 +/- 0.1%/d) (p < 0.02, Mann- Whitney U test). The absolute synthesis rate of PC in the beta group [1.6 +/- 0.3 micromol/kg/d] was increased by 128% above controls [0.7 +/- 0.2 micromol/kg/d] (p < 0.02). These data show that the synthesis of endogenous surfactant from plasma glucose as precursor is a slow process. It is shown, for the first time in vivo, that prenatal glucocorticosteroids stimulate the synthesis of surfactant PC in the very premature baboon.

Endogenous surfactant turnover in preterm infants measured with stable isotopes (Article)

1998-01-01T00:00:00Z

We studied surfactant synthesis and turnover in vivo in preterm infants using the stable isotope [U-13C]glucose, as a precursor for the synthesis of palmitic acid in surfactant phosphatidylcholine (PC). Six preterm infants (birth weight, 916 +/- 244 g; gestational age, 27.7 +/- 1.7 wk) received a 24-h [U-13C]glucose infusion on the first day of life. The 13C-enrichment of palmitic acid in surfactant PC, obtained from tracheal aspirates, was measured by gas chromatography-combustion interface-isotope ratio mass spectrometry. We observed a significant incorporation of carbon-13 from glucose into surfactant PC palmitate. PC palmitate became enriched after 19.4 +/- 2.3 (16.5 to 22.3) h and reached maximum enrichment at 70 +/- 18 (48 to 96) h after the start of the label infusion. The fractional synthesis rate (FSR) of surfactant PC palmitate from glucose was 2.7 +/- 1.3%/d. We calculated the absolute production rate of surfactant PC to be 4.2 mg/kg/d, and the half-life to be 113 +/- 25 (87 to 144) h. Data on endogenous surfactant production and turnover were obtained for the first time in human infants with the use of stable isotopes. This novel and safe method could be applied to address many important issues concerning surfactant metabolism in preterm infants, children, and adults.

Surfactant impairment after mechanical ventilation with large alveolar surface area changes and effects of positive end-expiratory pressure (Article)

1998-01-01T00:00:00Z

We have assessed the effects of overinflation on surfactant function and composition in rats undergoing ventilation for 20 min with 100% oxygen at a peak inspiratory pressure of 45 cm H2O, with or without PEEP 10 cm H2O (groups 45/10 and 45/0, respectively). Mean tidal volumes were 48.4 (SEM 0.3) ml kg-1 in group 45/0 and 18.3 (0.1) ml kg-1 in group 45/10. Arterial oxygenation in group 45/0 was reduced after 20 min compared with group 45/10 (305 (71) vs 564 (10) mm Hg); maximal compliance of the P-V curve was decreased (2.09 (0.13) vs 4.16 (0.35) ml cm H2O-1 kg-1); total lung volume at a transpulmonary pressure of 5 cm H2O was reduced (6.5 (1.0) vs 18.8 (1.4) ml kg-1) and the Gruenwald index was less (0.22 (0.02) vs 0.40 (0.05)). Bronchoalveolar lavage fluid from the group of animals who underwent ventilation without PEEP had a greater protein concentration (2.18 (0.11) vs 0.76 (0.22) mg ml-1) and a greater minimal surface tension (37.2 (6.3) vs 24.5 (2.8) mN m-1) than in those who underwent ventilation with PEEP. Group 45/0 had an increase in non-active to active total phosphorus compared with nonventilated controls (0.90 (0.16) vs 0.30 (0.07)). We conclude that ventilation in healthy rats with peak inspiratory pressures of 45 cm H2O without PEEP for 20 min caused severe impairment of pulmonary surfactant composition and function which can be prevented by the use of PEEP 10 cm H2O.

The regulation of CTP:Phosphocholine cytidylyltransferase in fetal type 2 cells (Doctoral Thesis)

1995-11-22T00:00:00Z

Respiratory distress syndrome (RDS), also known as hyaline membrane disease, is an important cause of neonatal and infant mortality. Together with congenital malformations, it is the leading cause of death in preterm infants and is responsible for serious morbidity in survivors, associated with high costs to society. Since 1959 it is known that RDS is caused by lung immaturity with concomitant surfactant deficiency. Numerous small studies and large multicenter trials have demonstrated decreased death rates and complications from RDS as a result of treatment with surfactant. Despite its success however, surfactant therapy is not a panacea. Recent meta-analyses from the available data do not show a consistent decrease in long term pulmonary complications such as bronchopulmonary dysplasia, nor in the major nonpulmonary complications such as intraventricular haemorrhage.