Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0728731 (prematurity)
 7,134 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dietary or chemical depletion of pulmonary glutathione in adult rats and mice, has been demonstrated to exacerbate the toxic effects of high oxygen concentrations. The present paper has examined this phenomenon in a guinea-pig model of prematurity, using the electrophilic agent diethylmaleic acid (DEM) to provide a transient (up to 12 h) pulmonary glutathione depletion. Full-term and 3-days preterm guinea-pig pups were studied to assess the possible role for glutathione deficiency as a mechanism mediating the increased susceptibility of the immature lung to oxygen free-radical damage. The administration of DEM to guinea-pig neonates depleted lung glutathione by 90% (term) or 68% (preterm) over 2 h. On exposure of pups to 95% oxygen for 48 h, DEM increased the incidence of oxygen-related death to 31% in term pups and 100% in preterm pups. Term pups exposed to hyperoxia and treated with DEM showed evidence of pulmonary injury, indicated by an influx of neutrophils into the lung airspaces, and elevated microvascular permeability. Control pups exposed to 95% oxygen were found to have uninjured lungs after 48 h. We conclude that glutathione is an essential component of the pulmonary antioxidant array in neonates. Glutathione may be of particular importance in the early phase of oxygen exposure. The deficiency of lung glutathione observed in preterm animals may account for their increased susceptibility to oxygen-induced pulmonary injury.
 ...
PMID:Depletion of pulmonary glutathione using diethylmaleic acid accelerates the development of oxygen-induced lung injury in term and preterm guinea-pig neonates. 802 13

The therapeutic efficacy of N-acetylcysteine (NAC) in the management of hyperoxia-induced lung injury was assessed using the preterm guinea pig model of prematurity. Preterm guinea pig pups were delivered by Caesarean section 3 days preterm, and exposed to either 21 or 95% oxygen for 72 hr. NAC (200 mg/kg body weight) or saline was injected twice daily. Bronchoalveolar lavage fluid (BALF) from hyperoxia-exposed pups contained significantly higher protein concentrations and an increased number of neutrophils. NAC partly ameliorated lung injury, preventing the increase in BALF protein concentration, which is generally associated with oedema. There was no effect on the movement of neutrophils into the lung airspaces in response to oxygen. Treatment with NAC had no effect on lung or liver glutathione (reduced) (GSH) concentrations either after 2 hr post-administration, or over the full 72 hr experimental period. An apparent resistance of the lung to increased synthesis or uptake of GSH was demonstrated by the lack of effect of direct administration of GSH, its isopropyl ester or 2-oxo-4-thiazolidine carboxylic acid. Oxygen exposure alone (95%) increased lung concentrations by 60-70%. It would, therefore, appear from this data that NAC may have potential as a future component of antioxidant therapy, although its effects are not mediated through increased GSH levels.
 ...
PMID:N-acetylcysteine ameliorates hyperoxic lung injury in the preterm guinea pig. 845 59

Respiratory distress in premature newborns is associated with deficiency of surfactant in the bronchoalveolar lining fluid; this may be influenced by a local deficiency of antioxidants. Severe L-buthionine-S,R-sulfoximine-induced depletion of glutathione (GSH, a major antioxidant) in rodents is associated with lung type 2 cell lamellar body damage and decreased concentrations in lung and bronchoalveolar lavage fluid (BALF) of phosphatidyl choline (a major component of surfactant). At birth, prematurely born newborns (30-34 weeks) had lower peripheral venous plasma GSH concentrations than term (> 36 weeks) babies; these levels decreased further with increasing prematurity (< 27 weeks, with respiratory distress). On day 2, the peripheral venous plasma GSH concentrations reached a nadir, and the lowest levels were found in the most premature newborns. Lymphocyte GSH concentrations were lowest on day 2 and day 7, and in prematures (< 27 weeks, with respiratory distress) remained below adult lymphocyte GSH levels for at least 4 weeks. At birth, prematures (< 27 weeks, with respiratory distress) had a central plasma arterio-venous (A-V) GSH gradient across the lung (an estimate of lung uptake of GSH) of 0.72 +/- 0.15 (mean +/- SD) mumol/L; on day 2, the A-V gradient did not change significantly (0.49 +/- 0.09 mumol/L). At birth, these prematures had markedly decreased BALF GSH concentrations (compared with adult levels), and they were not significantly changed during the first 4 weeks of life. These results suggest that GSH deficiency is present in prematures and that it increases with the degree of prematurity. At birth, GSH deficiency will compromise the lungs' defense against oxidative stress injury. Oxidative stress is likely to increase if hyperoxic treatment is given for respiratory distress in these infants.
 ...
PMID:Glutathione metabolism in newborns: evidence for glutathione deficiency in plasma, bronchoalveolar lavage fluid, and lymphocytes in prematures. 854 67

The imbalance between high oxidant loads and immature antioxidant defenses is associated with long-term complications of prematurity. Glutathione is a central element among the antioxidants. Depletion of pulmonary glutathione accelerates the development of oxygen-induced lung injury in neonatal animal models. After the observation that newborn infants exposed to oxygen have low glutathione levels, a study was designed to test the hypothesis that in neonates from a species susceptible to oxygen toxicity, the lethal effect of hyperoxia is related to a low availability of substrates for glutathione production rather than an impairment in synthetic activity. One-day-old guinea pigs, randomly assigned to room air or oxygen (>95%), were fed by their mothers (n = 16) or i.v. by dextrose (n = 14) or by total parenteral nutrition (TPN, n = 20). After 3 d, glutathione and activities of enzymes involved in maintaining intracellular glutathione levels were determined in lungs and liver. The lethal effect of oxygen (p < 0.05) observed in animals without TPN was not related to glutathione depletion, as oxygen induced a 33% increase in lung glutathione, positively correlated (r2 = 0.35) with enhanced synthesis. With TPN, the animals were protected against the lethal effects of hyperoxia and lung glutathione increased by 67% in oxygen. The results suggest that the glutathione demand by the lungs in the presence of an oxidant stimulus was met by the increased (p < 0.001) hepatic production supported by TPN. Under hyperoxic conditions, early nutritional support is of vital importance.
 ...
PMID:Survival of guinea pig pups in hyperoxia is improved by enhanced nutritional substrate availability for glutathione production. 1047 45

Prematurity has been associated with low glutathione (GSH) concentrations in bronchoalveolar lavage fluid as well as in leukocytes from tracheal aspirates and peripheral blood. To elucidate whether this is caused by deficient GSH synthesis, the expression and activity of gamma-glutamylcysteine synthetase (glutamate-cysteine ligase, GCS, EC 6.3.2.2), the rate-limiting enzyme for GSH synthesis, were measured from fetal, neonatal, and adult human liver, lung, and kidney samples. The highest activity was measured in the liver, in which mRNA expression of the catalytic GCS heavy and the regulatory light subunits, as well as activity, were, on average, similar in the various stages of development. Although GCS light subunit mRNA concentrations in the lung were higher in neonates than in fetuses and adults, enzyme activities were similar. In the adult kidney, mean enzyme activity was somewhat higher than in fetal or neonatal kidney, but this may be accounted for by the variation in the small number of samples. In conclusion, GCS is expressed and active already in the second trimester and thus low GSH concentrations found in preterm neonates appear not to be explained by deficient GSH synthesis. Other factors, such as limited availability of the GSH precursor cysteine or increased GSH consumption, may account for the lower concentrations of GSH found in preterm infants.
 ...
PMID:Expression of gamma-glutamylcysteine synthetase during development. 1067 57

Prematurity-mediated cerebral damage has been associated with oxidative stress. The aim of the present work was to study the possible role played by free oxygen radicals generated by mitochondrial respiratory function in cerebral injury in preterm neonates. Our results show that whereas total glutathione concentrations are similar in term and preterm neonates, the GSH/GSSG ratio decreases sharply in preterm neonates immediately after birth. This effect is not due to a lack of enzymes involved in GSH regeneration, such as glutathione reductase and glucose-6-phosphate dehydrogenase, but to a significant increase in free-radical generation in preterm rat brain as shown by the increase in lipoperoxidation. Because the mitochondrion is the main source of free radicals in the cell, mitochondrial respiratory function was studied in the brain of preterm neonates. Our results show that prematurity prevented the postnatal increases in complex II-III activity and ATP concentrations that occur in term neonates at 5 min after delivery. All these effects were counteracted by the oxygen supply, suggesting that the inhibition of mitochondrial function is caused by restricted oxygen availability. Consequently, cerebral damage associated with prematurity may be mediated by mitochondrial free-radical generation as a consequence of hypoxia undergone by preterm neonates at birth.
 ...
PMID:Oxidative stress in preterm rat brain is due to mitochondrial dysfunction. 1175 37

Increased airway smooth muscle (ASM) content is characteristic of infants with chronic lung disease of prematurity/bronchopulmonary dysplasia. Oxygen therapy, reactive oxygen species (ROS), and immature antioxidant defenses are major risk factors in chronic lung disease of prematurity/bronchopulmonary dysplasia, but their interrelationship is unclear. The direct effects of raised Po2 and modulation of ROS were examined on proliferation of cultured fetal human ASM cells. A bell-shaped relationship was found between Po2 and DNA synthesis induced by fetal bovine serum, platelet-derived growth factor, and basic fibroblastic growth factor, with peak responses occurring at 10-kPa Po2. Changes in DNA synthesis by Po2 did not occur in the absence of mitogen. ROS generation, estimated by dichlorodihydrofluorescein oxidation, was increased by mitogens but was unaffected by nonmitogens (bradykinin, histamine). There was an inverse relationship between ROS generation and Po2, and mitogen-induced ROS generation was substantially potentiated as the Po2 fell. H2O2 mimicked the effect of Po2 on fetal bovine serum-stimulated proliferation, whereas treatment with antioxidants (GSH, N-acetylcysteine) reduced it. These data demonstrate that increases in Po2 above levels found in utero modulate proliferation of fetal ASM cells but only in the presence of growth factors. They also strongly suggest that, under these conditions, proliferation is mediated in part by generation of ROS.
 ...
PMID:Oxygen regulates mitogen-stimulated proliferation of fetal human airway smooth muscle cells. 1238 46

Parenteral multivitamins (MVP) are linked to the generation of peroxides, which cause oxidant injury in lungs associated with alveolar remodelling linked to lung disease of prematurity. This study was to investigate the relationship between alveolar development and lung oxidant-antioxidant status as modulated by the mode of administration of multivitamins with total parenteral nutrition (TPN). Four groups of guinea pig pups received parenteral nutrition differing by 1) mode of MVP admixture: with amino acid solution (AA-MVP) or lipid emulsion (LIP-MVP); 2) light exposure: TPN exposed (LE) or shielded from light (LP). After 2 or 4 days of TPN, vitamins C and E, 8-isoprostaneF2alpha and alveolarization index were determined in lungs and GSSG/GSH in lungs and blood. Exposure to light and the mode of MVP admixture did not influence vitamin E and isoprostane levels. Blood glutathione redox potential was more oxidized in LE and LIP-MVP groups after 4-day infusions, whereas lung redox potential was more reduced in LE groups. LP and LIP-MVP had a beneficial effect, with higher number of alveoli. Globally, results indicate that in this model, alveolarization and modifications in lung redox potential are two independent events induced by light exposed TPN.
 ...
PMID:Influence of lung oxidant and antioxidant status on alveolarization: role of light-exposed total parenteral nutrition. 1847 54

Erythropoietin (Epo) has been used for many years in neonates for the treatment of anemia of prematurity. Epo has also been proposed for treatment of neonatal brain injury, as mounting evidence suggests neuroprotective properties for Epo. However, Epo's neuroprotective mechanism of action is poorly understood. In this study we hypothesized that Epo may confer neuroprotection by enhancing cellular redox defense brought about by cellular glutathione (GSH). This was examined in cultures of differentiated cortical neural stem cells and using the B104 cell line as model systems. Our data shows that Epo causes a time- and dose-dependent increase in expression and activity of system Xc(-), the transporter responsible for uptake of cystine for the production of glutathione. Cystine uptake increases 3-5 fold in differentiated neural stem cells and B104 cells treated with Epo. Exposure of cells to 100 microM kainate suppressed cellular GSH and caused excitotoxicity, but GSH levels and cell viability were completely restored by Epo in the continued presence of kainate. This rescue effect of Epo vanished if system Xc(-) was inhibited pharmacologically using S4-CPG in the presence of Epo leading to marked cell death of B104 cells and cultured mouse cortical neural stem cells. This could also be achieved using xCT siRNA to decrease xCT expression. This data suggests that system Xc(-) activity and protein expression are positively regulated by Epo directly explaining its neuroprotective effect.
 ...
PMID:Erythropoietin-induced neuroprotection requires cystine glutamate exchanger activity. 2010 5

Oxygen radicals are believed to contribute to typical diseases of prematurity, such as bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH), retinopathy of prematurity (ROP) and necrotising enterocolitis (NEC). Our aim was to investigate whether these disorders are associated with disturbances in antioxidant enzyme activities and with low trace elements, which are co-factors of antioxidant enzymes. 209 infants with birthweight less than 1000g were enrolled into a European multicentre randomised erythropoietin (rhEPO) trial; 155 developed one or more of the above mentioned diseases. We analysed Zn, Cu, Fe, Se in plasma and red blood cells (RBCs), superoxide dismutase (CuZn-SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in RBCs on the 3rd and 68th day of life. Zn, Fe, Se in plasma, and Se in RBCs decreased (p<0.01), and Zn in RBC (p<0.001), CuZn-SOD (p<0.01) and CAT increased (p<0.05), whereas GSH-Px remained unchanged. No differences were observed between the rhEPO and control groups. Antioxidant enzyme activities did not correlate with gestational age. In infants with BPD, IVH, ROP, or NEC, CuZn-SOD and CAT (p<0.05) were higher at day 68 than in infants without these diseases. CuZn-SOD and GSH-Px at 3 days and CuZn-SOD at 68 days correlated positively (p<0.05) with the duration of oxygen treatment. In conclusion, in ELBW infants, trace element concentrations decreased over the first 10 weeks of life. Lower trace element concentrations, did not affect the activities of CuZn-SOD, GSH-Px, and CAT. Typical diseases of prematurity were not associated with decreased antioxidant enzyme activities.
 ...
PMID:Trace elements and antioxidant enzymes in extremely low birthweight infants. 2041 69


1 2 Next >>