Attenuation of hyperoxic lung injury by the CYP1A inducer beta-naphthoflavone.
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Supplemental oxygen, frequently used in premature infants, has been implicated in the development of bronchopulmonary dysplasia (BPD). While the mechanisms of oxygen-induced lung injury are not known, reactive oxygen species (ROS) are most likely involved in the process. Here, we tested the hypothesis that upregulation of cytochrome P450 (CYP) 1A isoforms in lung and liver may lead to protection against hyperoxic lung injury. Adult male Sprague-Dawley rats were pretreated with the CYP1A inducer beta-naphthoflavone (beta-NF) (80 mg/kg/day), once daily for 4 days, followed by exposure to hyperoxic environment (O2 > 95%) or room air (normoxia) for 60 h. Pleural effusions were measured as estimates of lung injury. Activities of hepatic and pulmonary CYP1A1 were determined by measurement of ethoxyresorufin O-deethylation (EROD) activity. Northern hybridization and Western blot analysis of lung and liver were performed to assess mRNA and protein levels, respectively. Our results showed that beta-NF-treated animals, which displayed the highest pulmonary and hepatic induction in EROD activity (10-fold and 8-fold increase over corn oil (CO) controls, respectively), offered the most protective effect against hyperoxic lung injury, p < 0.05. Northern and Western blot analysis correlated well with enzyme activities. Our results showed an inverse correlation between pulmonary and hepatic CYP1A expression and the extent of lung injury, which supports the hypothesis that CYP1A enzyme plays a protective role against oxygen-mediated tissue damage. (+info)
Inhaled nitric oxide for premature infants with severe respiratory failure.
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BACKGROUND: Inhaled nitric oxide is a controversial treatment for premature infants with severe respiratory failure. We conducted a multicenter, randomized, blinded, controlled trial to determine whether inhaled nitric oxide reduced the rate of death or bronchopulmonary dysplasia in such infants. METHODS: We randomly assigned 420 neonates, born at less than 34 weeks of gestation, with a birth weight of 401 to 1500 g, and with respiratory failure more than four hours after treatment with surfactant to receive placebo (simulated flow) or inhaled nitric oxide (5 to 10 ppm). Infants with a response (an increase in the partial pressure of arterial oxygen of more than 10 mm Hg) were weaned according to protocol. Treatment with study gas was discontinued in infants who did not have a response. RESULTS: The rate of death or bronchopulmonary dysplasia was 80 percent in the nitric oxide group, as compared with 82 percent in the placebo group (relative risk, 0.97; 95 percent confidence interval, 0.86 to 1.06; P=0.52), and the rate of bronchopulmonary dysplasia was 60 percent versus 68 percent (relative risk, 0.90; 95 percent confidence interval, 0.75 to 1.08; P=0.26). There were no significant differences in the rates of severe intracranial hemorrhage or periventricular leukomalacia. Post hoc analyses suggest that rates of death and bronchopulmonary dysplasia are reduced for infants with a birth weight greater than 1000 g, whereas infants weighing 1000 g or less who are treated with inhaled nitric oxide have higher mortality and increased rates of severe intracranial hemorrhage. CONCLUSIONS: The use of inhaled nitric oxide in critically ill premature infants weighing less than 1500 g does not decrease the rates of death or bronchopulmonary dysplasia. Further trials are required to determine whether inhaled nitric oxide benefits infants with a birth weight of 1000 g or more. (+info)
Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide.
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BACKGROUND: Chronic lung disease and severe intraventricular hemorrhage or periventricular leukomalacia in premature infants are associated with abnormal neurodevelopmental outcomes. In a previous randomized, controlled, single-center trial of premature infants with the respiratory distress syndrome, inhaled nitric oxide decreased the risk of death or chronic lung disease as well as severe intraventricular hemorrhage and periventricular leukomalacia. We hypothesized that infants treated with inhaled nitric oxide would also have improved neurodevelopmental outcomes. METHODS: We conducted a prospective, longitudinal follow-up study of premature infants who had received inhaled nitric oxide or placebo to investigate neurodevelopmental outcomes at two years of corrected age. Neurologic examination, neurodevelopmental assessment, and anthropometric measurements were made by examiners who were unaware of the children's original treatment assignment. RESULTS: A total of 138 children (82 percent of survivors) were evaluated. In the group given inhaled nitric oxide, 17 of 70 children (24 percent) had abnormal neurodevelopmental outcomes, defined as either disability (cerebral palsy, bilateral blindness, or bilateral hearing loss) or delay (no disability, but one score of less than 70 on the Bayley Scales of Infant Development II), as compared with 31 of 68 children (46 percent) in the placebo group (relative risk, 0.53; 95 percent confidence interval, 0.33 to 0.87; P=0.01). This effect persisted after adjustment for birth weight and sex, as well as for the presence or absence of chronic lung disease and severe intraventricular hemorrhage or periventricular leukomalacia. The improvement in neurodevelopmental outcome in the group given inhaled nitric oxide was primarily due to a 47 percent decrease in the risk of cognitive impairment (defined by a score of less than 70 on the Bayley Mental Developmental Index) (P=0.03). CONCLUSIONS: Premature infants treated with inhaled nitric oxide have improved neurodevelopmental outcomes at two years of age. (+info)
NF-kappaB in tracheal lavage fluid from intubated premature infants: association with inflammation, oxygen, and outcome.
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OBJECTIVES: To determine if tracheal lavage concentrations of the transcription factor NF-kappaB, which is activated by risk factors associated with bronchopulmonary dysplasia (BPD) and induces expression of cytokines associated with BPD, is related to BPD in premature infants. DESIGN: Serial tracheal lavage samples from intubated premature infants were analysed for cell count and concentrations of interleukin (IL)8 and NF-kappaB, corrected for dilution by secretory component concentrations. SETTING: Level III university hospital neonatal intensive care unit. PATIENTS: Thirty three intubated infants (mean (SD) birth weight 903 (258) g, median gestation 27 weeks (range 24-31)) in the first 14 days of life. MAIN OUTCOME MEASURES: Tracheal effluent NF-kappaB, IL8, and cell counts, corrected for dilution by secretory component measurement. RESULTS: Square root transformed NF-kappaB concentrations were significantly related to signs of inflammation (cell count, p = 0.002; IL8, p = 0.019) and to simultaneous fraction of inspired oxygen in samples from the first 3 days of life (r = 0.512, p<0.003). Of the 32 subjects with samples in the first 3 days of life, the half who either died or had BPD had higher NF-kappaB concentrations than those without BPD (square root concentration 0.097 (0.043) v 0.062 (0.036) microg/microg protein/microg secretory component, p = 0.018). CONCLUSIONS: Tracheobronchial lavage NF-kappaB concentrations are related to lung inflammation, oxygen exposure, and pulmonary outcome in intubated preterm infants. NF-kappaB activation may be an early critical step leading to BPD. (+info)
Motor development of very low birthweight infants with chronic lung disease - a comparative study.
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INTRODUCTION: To determine whether chronic lung disease (CLD) influences specific aspects of motor development in infancy. MATERIALS AND METHODS: Twenty-nine very low birthweight infants with CLD at 36 weeks' post-conceptional age and 31 infants without CLD were evaluated at 8 months' and 24 months' corrected age using the Neurosensory Motor Development Assessment. Perinatal and neonatal characteristics of the infants with CLD and control infants were compared using the chi-square test for categorical variables and Student's t-test for continuous variables. The relationship between CLD and adverse outcome was measured by the odds ratio (OR) and its 95% confidence interval (CI). RESULTS: The overall developmental scores of the CLD infants were significantly different compared with control infants at 8 months. By 2 years of age, both groups of infants showed marked improvement in motor performance. However, differences persisted in the area of postural balance and sensory motor skills. Taking periventricular haemorrhage and periventricular leukomalacia into consideration, CLD contributed significantly to the occurrence of motor dysfunction at 8 months of age [odds ratio (OR), 7.4; 95% confidence interval (CI), 2.1 to 26.5]. The impact of CLD on motor development remained substantial, though not statistically significant (OR, 3.7; 95% CI, 0.4 to 37.9) at 2 years of age. CONCLUSION: CLD has a definite effect on motor development. The pathologic influence of CLD on motor development remains speculative but results of this study emphasise the need for careful neurodevelopmental follow-up of infants with CLD, whether or not these infants suffer intraventricular haemorrhage or periventricular leukomalacia. (+info)
Characterization of ureaplasmas isolated from preterm infants with and without bronchopulmonary dysplasia.
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A PCR assay was used to analyze endotracheal aspirates from preterm infants for Ureaplasma parvum versus U. urealyticum. U. parvum was detected more often than U. urealyticum. There was no significant difference or trend in the prevalence of either species between infants with or without bronchopulmonary dysplasia when isolated alone. (+info)
Imbalance between cysteine proteases and inhibitors in a baboon model of bronchopulmonary dysplasia.
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RATIONALE: Bronchopulmonary dysplasia (BPD) continues to be a major morbidity in preterm infants. The lung pathology in BPD is characterized by impaired alveolar and capillary development. An imbalance between proteases and protease inhibitors in association with changes in lung elastic fibers has been implicated in the pathogenesis of BPD. OBJECTIVE: To investigate the expression and activity levels of papain-like lysosomal cysteine proteases, cathepsins B, H, K, L, S, and their inhibitors, cystatins B and C, in a baboon model of BPD. METHODS: Real-time reverse transcriptase-polymerase chain reaction, immunohistochemistry, immunoblotting, active site labeling of cysteine proteases, and in situ hybridization were performed. MEASUREMENTS AND MAIN RESULTS: The steady-state mRNA and protein levels of all cathepsins were significantly increased in the lung tissue of baboons with BPD. In contrast, the steady-state mRNA and protein levels of two major cysteine protease inhibitors, cystatin B and C, were unchanged. Correlating with these alterations, the activity of cysteine proteases in lung tissue homogenates and bronchoalveolar lavage fluid was significantly higher in the BPD group. The levels of cathepsin B, H, and S increased and cathepsin K decreased with advancing gestation. All cathepsins, except for cat K, were immunolocalized to macrophages in BPD. In addition, cathepsin H and cystatin B were colocalized in type 2 alveolar epithelial cells. Cathepsin L was detected in some bronchial epithelial, endothelial, and interstitial cells. Cathepsin K was localized to some perivascular cells by in situ hybridization. CONCLUSIONS: Cumulatively, these findings demonstrate an imbalance between cysteine proteases and their inhibitors in BPD. (+info)
Growth of pulmonary microvasculature in ventilated preterm infants.
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RATIONALE: Density-based morphometric studies have demonstrated decreased capillary density in infants with bronchopulmonary dysplasia (BPD) and in BPD-like animal models, leading to the prevailing view that microvascular development is disrupted in BPD. OBJECTIVE: To perform a comprehensive analysis of the early and late effects of ventilation on pulmonary microvascular growth in preterm infants. METHODS: Postmortem lung samples were collected from ventilated preterm infants who died between 23 and 29 wk ("short-term ventilated") or between 36 and 39 wk ("long-term ventilated") corrected postmenstrual age. Results were compared with age-matched infants or stillborn infants ("early" and "late" control subjects). Microvascular growth was studied by anti-platelet endothelial cell adhesion molecule (PECAM)-1 immunohistochemistry, quantitative stereology, analysis of endothelial cell proliferation, and Western blot analysis of pulmonary PECAM-1 protein levels. MEASUREMENTS: Measurements were made of capillary density, volume of air-exchanging parenchyma, volume of microvascular endothelial cells, Ki67 labeling index of endothelial cells, and PECAM-1/actin protein levels. MAIN RESULTS: Lungs of long-term ventilated infants showed a significant (more than twofold) increase in volume of air-exchanging parenchyma and a 60% increase in total pulmonary microvascular endothelial volume compared with late control subjects, associated with 60% higher pulmonary PECAM-1 protein levels. The marked expansion of the pulmonary microvasculature in ventilated lungs was, at least partly, attributable to brisk endothelial cell proliferation. The microvasculature of ventilated lungs appeared immature, retaining a saccular architectural pattern. CONCLUSIONS: The pulmonary microvasculature of ventilated preterm infants displayed marked angiogenesis, nearly proportionate to the growth of the air-exchanging lung parenchyma. These results challenge the paradigm of microvascular growth arrest as a major pathogenic factor in BPD. (+info)