endothelin-1 and Bronchopulmonary-Dysplasia

Bronchopulmonary dysplasia (BPD) has been defined as a requirement for oxygen for more than 28 days because of chronic pulmonary changes, usually in a premature infant. About 50 per cent of very low birth weight (VLBW) infants who weigh 1 kg at birth and who survive 28 days will develop BPD. Since 80 per cent of fetal accretion of magnesium occurs during the third trimester, this population is also at risk for magnesium deficiency. This paper reviews evidence for a role of magnesium deficiency in the pathogenesis of BPD. Pathology in BPD that may be caused or aggravated by magnesium deficiency is noted. Agents or mediators that are increased in BPD and in BPD include: oxygen free radicals; the inflammatory cytokines interleukin (IL)-1 and IL-6, and tumour necrosis factor-alpha; vaso- and bronchoconstrictors thromboxane A2 (TXA2) and serotonin: vasoconstrictor, endothelin-1 (ET-1); and bronchoconstrictor, histamine. Magnesium deficiency increases the susceptibility of cells and tissues to peroxidation, worsens the inflammatory reaction, reduces the immune response, exaggerates catecholamine release in stress, and diminishes energy metabolism. Possibly because of the danger of magnesium toxicity and the difficulty in studying the preterm VLBW neonate, little is known about magnesium supplementation in this group. Such information must be gained through controlled studies on the effect of antepartum exposure to maternally administered magnesium sulphate on the VLBW infant, through carefully monitored postnatal administration of magnesium in an intensive care setting, or through evaluations of combined pre- and postnatal supplementation.

Topics: Animals; Bronchopulmonary Dysplasia; Chemokines; Endothelin-1; Free Radicals; Humans; Hydroxyeicosatetraenoic Acids; Immunoglobulins; Infant, Newborn; Infant, Very Low Birth Weight; Magnesium Deficiency; Nitric Oxide; Substance P; Thromboxane A2; Tumor Necrosis Factor-alpha

Bronchopulmonary dysplasia (BPD) is a major complication in preterm infants <32 weeks. We aimed to assess whether plasma levels of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET-1) predict respiratory morbidity.. This was a prospective, two-center, observational cohort study. MR-proANP and CT-proET-1 were measured at day 7 (±2) of life. Associations with duration of supplemental oxygen and the composite outcome of moderate or severe BPD or death (BPD/death) were investigated.. Two hundred and twenty-nine infants <32 weeks were included (median gestational age [GA] 29.6 weeks [interquartile range 29.0-30.7], median birth weight 1150 g [IQR 840-1410]). MR-proANP and CT-proET-1 were associated with the duration of supplemental oxygen in univariable analysis (both p < 0.001) but not after adjusting for co-factors. Infants with BPD/death showed higher plasma levels of MR-proANP (623.50 pmol/L [IQR 458.50-881.38] vs. 308.35 pmol/L [IQR 216.72-538.10]; p < 0.001) and CT-proET-1 (255.40 pmol/L [IQR 202.60-311.15] vs. 198.30 pmol/L [IQR 154.70-297.95]; p = 0.015) compared to infants without BPD/death. Levels of both biomarkers were significantly associated with BPD/death in univariable models but not after adjusting for co-factors.. MR-proANP and CT-proET-1 are associated with the duration of supplemental oxygen and the composite outcome BPD/death, but their prognostic value does not complement that of clinical risk factors.. Plasma levels of MR-proANP and CT-proET-1, measured on day 7 of life (±2 days) are associated in univariable analyses with duration of supplemental oxygen and the combined outcome of BPD or death in VLGA infants. Associations between both biomarkers and respiratory morbidity do not persist in multivariable models, in particular when gestational age is included. MR-proANP and CT-proET-1 have limited additional value to predict respiratory morbidity in VLGA infants compared to clinical parameters.

Topics: Atrial Natriuretic Factor; Biomarkers; Bronchopulmonary Dysplasia; Endothelin-1; Humans; Infant; Infant, Newborn; Infant, Premature; Morbidity; Natriuretic Peptides; Oxygen; Peptide Fragments; Prospective Studies; Vasodilator Agents

To assess the prognostic value of early echocardiographic indices of right ventricular function and vasoactive peptides for prediction of bronchopulmonary dysplasia (BPD) or death in very preterm infants.. Prospective study involving 294 very preterm infants (median [IQR] gestational age 28.4 [26.4-30.4] weeks, birth weight 1065 [800-1380] g), of whom 57 developed BPD (oxygen supplementation at 36 weeks postmenstrual age) and 10 died. Tricuspid annular plane systolic excursion (TAPSE), right ventricular index of myocardial performance (RIMP), plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) were measured on day 7 of life.. RIMP was significantly increased (median [IQR] 0.3 [0.23-0.38] vs 0.22 [0.15-0.29]), TAPSE decreased (median [IQR] 5.0 [5.0-6.0] vs 6.0 [5.4-7.0] mm), MR-proANP increased (median [IQR] 784 [540-936] vs 353 [247-625] pmol/L), and CT-proET1 increased (median [IQR] 249 [190-345] vs 199 [158-284] pmol/L) in infants who developed BPD or died, as compared to controls. All variables showed significant but weak correlations with each other (rS -0.182 to 0.359) and predicted BPD/death with similar accuracy (areas under receiver operator characteristic curves 0.62 to 0.77). Multiple regression revealed only RIMP and birth weight as independent predictors of BPD or death.. Vasoactive peptide concentrations and echocardiographic assessment employing standardized measures, notably RIMP, on day 7 of life are useful to identify preterm infants at increased risk for BPD or death.

Topics: Area Under Curve; Atrial Natriuretic Factor; Bronchopulmonary Dysplasia; Echocardiography; Endothelin-1; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Male; Prospective Studies; ROC Curve; Up-Regulation; Ventricular Function, Right

We aimed to investigate if endothelin 1 concentration at day 3 postnatal age could be used as a predictive marker for development of bronchopulmonary dysplasia in preterm neonates with respiratory distress syndrome.. This prospective observational study was done on 69 preterm neonates with gestational ages between 28 and 34 weeks and diagnosed as having respiratory distress syndrome. Serum concentrations of endothelin 1 was measured for all patients at day 3 of life and they were divided into BPD and No-BPD groups according to whether they developed bronchopulmonary dysplasia or not.. A total of 17 infants were in the BPD group and 52 infants were in the No-BPD group. Serum endothelin 1 was significantly higher in the BPD group (435.39±172.88) compared with the No-BPD group (302.65±49.32) (p < 0.001). Serum endothelin 1 correlated significantly with days spent on mechanical ventilation (r = 0.379, p = 0.022) and days spent on CPAP (r = 0.391, p = 0.001). A serum endothelin 1 cut off value of 302.7 ng/L could predict preterm that will develop bronchopulmonary dysplasia with a sensitivity of 88.24%, and specificity of 61.54%.. Serum endothelin 1 is significantly increased at day 3 of life in preterm neonates with respiratory distress syndrome who later develop bronchopulmonary dysplasia (BPD). It seems to be a promising predictive marker for BPD but further studies are needed to find the appropriate time for its measurement.

Topics: Biomarkers; Bronchopulmonary Dysplasia; Decision Support Techniques; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Male; Prospective Studies; Respiratory Distress Syndrome, Newborn; Severity of Illness Index

Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants. Clinical prediction of BPD at an early stage in life is difficult. Plasma proendothelin-1 (CT-proET-1) is a lung injury biomarker in pulmonary hypertension and respiratory distress.. To assess the prognostic ability of CT-proET-1 in BPD.. In 227 prospectively enrolled preterm infants born at <32 weeks gestational age (GA), plasma CT-proET-1 was measured at birth, day of life (DOL) 2, 3, 6 and 28, and at 36 weeks postmenstrual age (PMA). BPD was defined as mild in infants requiring supplemental oxygen at DOL 28 and moderate/severe in those requiring it at 36 weeks PMA.. The predictive ability of CT-proET-1 for any BPD was poor at birth [area under the ROC curve (AUC) 0.654, 95% CI 0.494-0.814], moderate at DOL 2 and 3 (AUC 0.769, 95% CI 0.666-0.872) and excellent at DOL 6 (AUC 0.918, 95% CI 0.840-0.995). Multivariable regression analysis revealed that CT-proET-1 levels at DOL 2, 3, 6 and 28 were strongly related to the duration of oxygen supplementation, independently of GA and the duration of respiratory support.. CT-proET-1 is a novel promising biomarker for predicting the development of BPD in preterm infants when measured at the end of the first week of life.

Topics: Biomarkers; Bronchopulmonary Dysplasia; Endothelin-1; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Male; Multivariate Analysis; Oxygen; Peptide Fragments; Prospective Studies; Regression Analysis

Plasma concentrations of the stable endothelin-1 precursor, C-terminal portion of the endothelin-1 precursor, determined prospectively in 293 newborn infants (gestational age, 24-41 weeks) at birth and on day 3 of life were unrelated to gestational age at birth, but strongly associated with respiratory distress when measured on day 3 of life.

Topics: Bronchopulmonary Dysplasia; Endothelin-1; Fetal Blood; Gestational Age; Humans; Infant, Newborn; Respiratory Distress Syndrome, Newborn

In addition to the immaturity of air sacs and surfactant deficiency, preterm infants with respiratory distress syndrome (RDS) have abnormalities in the pulmonary vascular bed. We aimed to study two known modulators of pulmonary vessels: endothelin-1 (ET-1) and L-arginine. We hypothesized that plasma concentrations of ET-1 and L-arginine could correlate with the severity of RDS. We prospectively studied 71 preterm infants (gestational age = 29 to 35 weeks) with and without RDS. We measured plasma ET-1 by enzyme-linked immunosorbent assay and L-arginine by spectrophotometry. Infants who continued to require oxygen support or died by day of life 28 were considered to have bronchopulmonary dysplasia (BPD). ET-1 concentrations were significantly higher in RDS infants ( p = 0.039) than controls. Among infants with RDS, it was significantly higher in those who later developed BPD ( p = 0.026). L-arginine was significantly lower in RDS infants ( p = 0.001), but did not differ between BPD and non-BPD infants ( p = 0.19). There was no correlation between L-arginine and ET-1 ( r = 0.1, p = 0.41). The acute phase of RDS is associated with increased plasma concentrations of ET-1 and decreased L-arginine. Infants who later developed BPD had higher plasma ET-1 at birth. Concentrations of ET-1 and L-arginine did not correlate.

Topics: Arginine; Bronchopulmonary Dysplasia; Disease Progression; Endothelin-1; Female; Humans; Infant, Newborn; Infant, Premature; Logistic Models; Male; Prospective Studies; Respiratory Distress Syndrome, Newborn; Severity of Illness Index

Neonatal respiratory distress syndrome can progress to bronchopulmonary dysplasia (BPD), a serious pulmonary fibrotic disorder. Given the involvement of the extrinsic coagulation cascade in animal models of lung fibrosis, we examined its role in BPD. We observed a higher number of neutrophils expressing tissue factor (TF) in bronchoalveolar lavage fluid (BALF) from infants with BPD than from those with uncomplicated respiratory distress syndrome together with a parallel decrease in TF and connective tissue growth factor (CTGF) in BALF supernatants during the disease course. The involvement of coagulation in the fibrotic process associated with BPD was further evaluated by treating primary human colonic myofibroblasts with BALF supernatants from infants with BPD. These human colonic myofibroblasts demonstrated an enhanced C5a- and thrombin-dependent migration. Moreover, they expressed TF in an endothelin-1-dependent manner, with subsequent activation of the extrinsic coagulation cascade and CTGF production mediated by protease-activator receptor-1 signaling. These data provide a novel mechanism for the development of BPD and indicate that endothelin-1 signaling contributes to fibrosis by upregulating a TF/thrombin amplification loop responsible for CTGF production, and offer novel and specific therapeutic targets for pulmonary fibrotic disease.

Topics: Blotting, Western; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Cells, Cultured; Colon; Complement C5a; Connective Tissue Growth Factor; Endothelin-1; Female; Fibrosis; Green Fluorescent Proteins; Humans; Immunohistochemistry; Infant, Newborn; Lung; Male; Microscopy, Fluorescence; Myofibroblasts; Receptor, Anaphylatoxin C5a; Receptor, PAR-1; Receptors, Complement; Respiratory Distress Syndrome, Newborn; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Thrombin; Thromboplastin

Basic fibroblast growth factor (bFGF or FGF-2), vascular endothelial growth factor (VEGF), and endothelin-1 (ET-1) are peptide growth factors (PGF) mediating normal lung development, maturation, injury, and repair. These PGF may therefore be involved in the pathogenesis of bronchopulmonary dysplasia (BPD). We hypothesized that elevated levels of these PGF in tracheal aspirates would be associated with a) BPD and/or death; b) markers of cell injury and apoptosis; and c) chorioamnionitis, a risk factor for BPD. Tracheal aspirates collected in 29 preterm (<34 wk gestation, 500-2000 g birth weight), mechanically ventilated infants on d 1 of life were assayed for PGF and histone-associated DNA fragments by ELISA and for LDH by enzyme assay. Clinical and pathologic examination was performed for chorioamnionitis. BPD was defined as oxygen requirement/mechanical ventilation at 28 d postnatal age. The birth weight (mean +/- SE) was 1009 +/- 85 g and median gestational age was 26 wk (range, 22-33). Eighteen infants died or developed BPD. bFGF levels were elevated in infants who died or developed BPD [median (25%,75%) level of 36 (23, 44) pg/mL versus 14 (6, 30) in the survivors without BPD, p = 0.01]. bFGF levels correlated with apoptosis (r = 0.73, p < 0.001) and LDH levels (r = 0.59, p < 0.001). VEGF and ET-1 levels were not associated with apoptosis or with BPD/death. PGF levels were not associated with chorioamnionitis. We conclude that elevated bFGF levels in the preterm trachea correlate with BPD/death and markers of cell injury and apoptosis but not with chorioamnionitis. We speculate that bFGF may play a role in the development of BPD.

Topics: Bronchopulmonary Dysplasia; Endothelial Growth Factors; Endothelin-1; Epithelial Cells; Female; Fibroblast Growth Factor 2; Growth Substances; Humans; Infant; Infant, Newborn; Infant, Premature; Intercellular Signaling Peptides and Proteins; Lymphokines; Male; Neutrophils; Peptides; Prospective Studies; Respiration, Artificial; Suction; Trachea; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Endothelin-1 (ET-1) is a novel and potent endothelium-derived vasoconstriction peptide present in human plasma. In this study, plasma ET-1 concentrations were determined and their physiological significance was evaluated in Taiwanese neonates with respiratory distress.. Sixty newborn infants consisting of 22 with respiratory distress syndrome (RDS), 13 with transient tachypnea of newborn (TTNB), 4 with meconium aspiration syndrome, 10 healthy preterm and 11 healthy full-term infants were included for plasma ET-1 determination. Plasma ET-1 levels were measured by enzyme immunoassay at the of age of 1 day. For those who were diagnosed with RDS, plasma ET-1 concentrations were scheduled for evaluation at the ages of 1, 2, 3, 7, 14, 28, and 35 days as long as oxygen was being used.. On the first day of life, there was no significant difference in plasma ET-1 concentrations between healthy preterm and term infants (3.92 +/- 0.88 vs. 3.56 +/- 1.98 pg/mL, p = 0.606). However, plasma ET-1 concentrations of infants with RDS were significantly higher than those with TTNB (6.46 +/- 0.58 vs. 3.77 +/- 1.29 pg/mL, p < 0.001). In RDS infants, plasma ET-1 concentrations showed no significant difference between those who developed bronchopulmonary dysplasia (BPD, N = 4) and those who recovered (non-BPD, n = 18) (7.84 +/- 1.85 vs. 5.81 +/- 2.76 pg/mL, p = 0.242).. Plasma ET-1 concentrations were similar in preterm and term infants. ET-1 concentrations were higher in infants with RDS than in infants with TTNB, which suggests that plasma ET-1 levels can be useful in the differential diagnosis. However, the plasma ET-1 concentrations can not be a predictor for BPD.

Topics: Birth Weight; Bronchopulmonary Dysplasia; Endothelin-1; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Meconium Aspiration Syndrome; Respiratory Distress Syndrome, Newborn

Newborn rats exposed to 60% O(2) for 14 d demonstrated a bronchopulmonary dysplasia-like lung morphology and pulmonary hypertension. A 21-aminosteroid antioxidant, U74389G, attenuated both pulmonary hypertension and macrophage accumulation in the O(2)-exposed lungs. To determine whether macrophage accumulation played an essential role in the development of pulmonary hypertension in this model, pups were treated with gadolinium chloride (GdCl(3)) to reduce lung macrophage content. Treatment of 60% O(2)-exposed animals with GdCl(3) prevented right ventricular hypertrophy (p < 0.05) and smooth muscle hyperplasia around pulmonary vessels, but had no effect on morphologic changes in the lung parenchyma. In addition, GdCl(3) inhibited 60% O(2)-mediated increases in endothelin-1, 8-isoprostane, and nitrotyrosine residues. Organotypic cultures of fetal rat distal lung cells were subjected to cyclical mechanical strain to assess the potential role of GdCl(3)-induced blockade of stretch-mediated cation channels in these effects. Mechanical strain caused a moderate increase of endothelin-1 (p < 0.05), which was unaffected by GdCl(3), but had no effect on 8-isoprostane or nitric oxide synthesis. A critical role for endothelin-1 in O(2)-mediated pulmonary hypertension was confirmed using the combined endothelin receptor antagonist SB217242. We concluded that pulmonary macrophage accumulation, in response to 60% O(2), mediated pulmonary hypertension through up-regulation of endothelin-1.

Topics: Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Cell Movement; Cells, Cultured; Dinoprost; Endothelin-1; F2-Isoprostanes; Gadolinium; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Infant, Newborn; Macrophages, Alveolar; Oxygen; Rats; Rats, Sprague-Dawley; Tyrosine

To determine whether endothelin-1 (ET-1) in tracheal aspirates (TA) is a specific marker for acute lung injury in preterm infants with respiratory distress syndrome (RDS) who progress to bronchopulmonary dysplasia (BPD); and to investigate the relationship between TA ET-1 and the proinflammatory cytokines, interleukin-6 (IL-6) and IL-8, as early mediators of BPD.. We measured TA ET-1, IL-6, and IL-8 levels in preterm infants whose lungs were mechanically ventilated for RDS, categorized into two groups, BPD or non-BPD, on the basis of oxygen requirement at 36 weeks' postconceptional age.. A total of 106 TA samples were obtained from 34 infants with gestational ages ranging from 24 to 28 weeks on days 1, 3, 5, and 7 of life. There was a wide range of ET-1 concentration. TA ET-1 levels were significantly elevated on days 1, 3, and 7 in infants in whom BPD developed, in comparison with the non-BPD group (Mann-Whitney U test: p < 0.01). TA IL-8 levels were elevated on days 1, 3, 5, and 7 in the BPD group (p < 0.01); TA IL-6 levels were elevated (p < 0.05) only on day 5. There was a similarity in pattern of increase of TA ET-1 and TA IL-8 levels in the BPD group, with both being elevated in the first 24 hours of life and through the first week. There was no correlation between ET-1 and IL-8 values.. Early significant increase in the TA ET-1 and IL-8 concentrations in preterm infants with acute lung injury correlates with subsequent progression to BPD.

Topics: Biomarkers; Bronchopulmonary Dysplasia; Case-Control Studies; Endothelin-1; Female; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Male; Respiration, Artificial; Time Factors; Trachea

The purpose of this study was to clarify the role of endothelin (ET)-1 in the development of bronchopulmonary dysplasia (BPD). Tracheal aspirates were obtained from 27 newborn babies with respiratory distress (13 with BPD and 14 without BPD) who were mechanically ventilated. Production of superoxide anion (O2-) by rabbit alveolar macrophages was determined by preincubation with the tracheal aspirate supernatant (TAS) and stimulation with phorbol myristate acetate (PMA). O2- production was demonstrated only when PMA was added to the experimental system and was enhanced with TAS of infants who later developed BPD compared with TAS from infants without BPD. The effects of ET-1 and ET-3 on O2- production and the blockade by anti-ET-1 antibody and BQ123 (ET A receptor antagonist) were also examined. The enhancing effect was blocked by either anti-ET-1 antibody or BQ123. PMA-stimulated production of O2- increased when cells were preincubated with several doses of ET-1 (5 x 10(-13) to 2 x 10(-12) M), whereas ET-3 was without effect. TAS contained significant amounts of immunoreactive ET-1, and there was a close positive correlation (r = 0.764) between the activity of O2- production and immunoreactive ET-1 levels in TAS samples. These results may be interpreted to indicate that ET-1 synthesized by and secreted from tracheal epithelial cells and/or alveolar macrophages has a priming effect on alveolar macrophages to produce O2-, thus possibly contributing to the development of BPD.

Topics: Albumins; Animals; Anions; Bronchoalveolar Lavage; Bronchopulmonary Dysplasia; Cells, Cultured; Endothelin-1; Endothelin-3; Humans; Infant, Newborn; Macrophages, Alveolar; Rabbits; Superoxides