leukotriene-e4 and Bronchopulmonary-Dysplasia

Inflammation plays an important role in the pathogenesis of bronchopulmonary dysplasia (BPD), but the exact nature of this inflammatory process is incompletely understood. Older infants with established BPD have higher levels of urinary leukotriene E(4) (LTE(4)) compared to healthy infants of the same age. This suggests that cysteinyl leukotrienes may play a role in the abnormalities seen in BPD.. To measure urinary LTE(4) levels during the first month of life in premature infants, and to determine whether there are significant differences in premature infants who develop BPD, as compared to those who do not develop BPD.. Prospective, blinded, controlled study.. Neonatal ICUs of a tertiary-care university hospital.. Thirty-seven premature infants (< 33 weeks of gestational age) were enrolled prospectively at birth. Urinary LTE(4) levels were measured blinded, using a standard radioimmunoassay technique at 2 days, 7 days, and 28 days of life. At 1 month of age, infants were classified as with or without BPD, based on need for supplemental oxygen, and characteristic chest radiographs. Clinical features and urinary LTE(4) were compared between the two groups.. Mean +/- SD gestational age was 29 +/- 2.6 weeks. None of the infants had a family history of asthma. Thirteen of 37 infants were classified as having BPD at 28 days after birth. Mean gestational age in infants who developed BPD was 27 +/- 2.4 weeks, compared to 30 +/- 2 weeks in infants who did not develop BPD (p < 0.05). In infants with BPD, mean urinary LTE(4) levels of urinary creatinine were 1,762 +/- 2,003 pg/mg, 1,236 +/- 992 pg/mg, and 5,541 +/- 5,146 pg/mg at days 2, 7, and 28, respectively, compared to 1,304 +/- 1,195 pg/mg, 1,158 +/- 1,133 pg/mg, and 2,800 +/- 2,080 pg/mg in infants without BPD. LTE(4) levels at 2 days, 7 days, and 28 days did not correlate with the subsequent development of BPD. LTE(4) levels at day 28 were significantly higher than LTE(4) levels at day 2 and day 7 in both groups, even after correcting for gestational age or birth weight (p < 0.05). There was significant inverse correlation between LTE(4) levels at day 2 with gestational age and birth weight (p < 0.05). All 13 infants with BPD received steroid pulses, compared to 3 of 26 infants without BPD. Gestational age and use of postnatal steroid pulses, diuretics, and theophylline (for apnea of prematurity) were significantly associated with each other and with the subsequent development of BPD.. Urinary LTE(4) levels measured on the second day of life in very-low-birth-weight infants inversely correlate with gestational age and birth weight. Urinary LTE(4) levels may reflect lung injury and/or inflammation in premature infants, not necessarily related to BPD as it is presently defined.

Topics: Biomarkers; Birth Weight; Bronchopulmonary Dysplasia; Female; Gestational Age; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Leukotriene E4; Male; Prospective Studies

To explore the correlation of urinary cysteinyl leukotriene E4 (CysLTE4) and diagnosis of bronchopulmonary dysplasia (BPD) in premature infants.. One hundred and fifty-eight newborn infants were consecutively admitted to the neonatal intensive care units of First Affiliated Hospital of Nanjing Medical University from November 2014 to October 2015.The infants were divided into 3 groups according to the diagnosis on discharge.Sixty-one term infants were classified as having no pulmonary diseases, 52 premature infants were classified as without BPD, and 45 premature infants with BPD were diagnosed at 28 d after birth.Urinary CysLTE4 levels of newborns within 3 days after birth were measured in a blinded way by enzyme- linked immunosorbent assay and were compared among 3 groups, and were evaluated for the diagnostic value and the correlation of gestational age and birth weight.Statistical analysis was performed using correlation analysis, one-way analysis of variance and χ(2) test etc.. In infants with BPD, the mean urinary CysLTE4 level was (191.0±29.3) ng/L which significantly higher than the premature group without BPD ((164.1±22.7) ng/L) and term infant group ((151.6±41.9) ng/L, F=18.70, P<0.05). Urinary CysLTE4 level within 3 days of life in newborn inversely correlated with gestational age and birth weight (Pearson=-0.33, -0.38, P<0.01). The area under the curve was 0.78, 95%CI: 0.70-0.86, P<0.01, when cutoff was 187.7 ng/L, with Youden index 0.59, sensitivity 77.8% and specificity 81.4%, respectively.. Urinary CysLTE4 level is up-regulated in BPD infants within early days of life which may be a useful biomarker of early diagnoses of BPD.

Topics: Biomarkers; Birth Weight; Bronchopulmonary Dysplasia; Female; Gestational Age; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Leukotriene E4; Male

Currently, bronchopulmonary dysplasia (BPD) occurs almost exclusively in pre-term infants. In addition to prematurity, other factors like oxygen toxicity and inflammation can contribute to the pathogenesis. This study aimed to compare urinary inflammatory and oxidative stress markers between the no/mild BPD group and moderate/severe BPD group and between BPD cases with significant early lung disease like respiratory distress syndrome (RDS) ('classic' BPD) and with minimal early lung disease ('atypical' BPD). A total of 60 patients who were a gestational age < 30 weeks or a birth weight < 1250 g were included. Urine samples were obtained on the 1(st), 3(rd) and 7(th) day of life and measured the levels of leukotriene E(4) (LTE(4)) and 8-hydroxydeoxyguanosine (8-OHdG). The 8-OHdG values on the 3(rd) day showed significant correlation to duration of mechanical ventilation. The 8-OHdG levels on the 7(th) day were the independent risk factor for developing moderate/severe BPD. In 'classic' BPD, the 8-OHdG values on the 3(rd) day were higher than those of 'atypical' BPD. In 'atypical' BPD, the LTE(4) values on the 7(th) day were higher than the values in 'classic' BPD. These results suggest that oxidative DNA damage could be the crucial mechanism in the pathogenesis of current BPD and the ongoing inflammatory process could be an important mechanism in 'atypical' BPD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Bronchopulmonary Dysplasia; Deoxyguanosine; Female; Humans; Infant; Infant, Newborn; Infant, Very Low Birth Weight; Inflammation; Leukotriene E4; Male; Oxidative Stress; Statistics as Topic

We examined whether lipid mediators have a causal role in neonatal hyperoxia-induced lung damage, specifically, airway remodeling and hyperresponsiveness. Newborn rat pups were exposed to hyperoxia (> 95% O2 from Days 4 to 14 and 65% from Days 14 to 32) or normoxia. The 5-lipoxygenase inhibitor, LTD4 receptor antagonist, and inhibitor of platelet-activating factor synthesis, Wy-50,295 (30 mg/kg), or vehicle was administered daily from Days 3 to 32. Oxygen exposure significantly increased (p < 0.05) the production of one potential lipid mediator group, peptido-LTs, from explanted lung slices and large airways from 2-wk-old rat pups. At 4 wk, only the large airway tissue output showed significant elevation because of oxygen exposure. At both ages, Wy-50,295 significantly decreased (p < 0.05) the production of peptido-LTs in the lung and large airways of oxygen-exposed pups. Pulmonary function and airway wall morphometry were studied in 5-wk-old rat pups 2 to 3 d after oxygen exposure and drug administration ceased. The resistance change in response to methacholine (0 to 20 microg/kg body weight given intravenously) was greater (p < 0.02) in oxygen-exposed animals. Oxygen exposure caused significant (60% increase) smooth muscle thickening (p < 0.05). Wy-50,295 prevented the oxygen-induced airway hyperresponsiveness and smooth muscle thickening. We conclude that chronic hyperoxic exposure causes an increase in pulmonary production of at least one lipid mediator, peptido-LTs, from newborn rats and that this is associated with airway smooth muscle layer thickening and, consequently, airway hyperresponsiveness.

Topics: Animals; Animals, Newborn; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchopulmonary Dysplasia; Humans; Infant, Newborn; Leukotriene C4; Leukotriene D4; Leukotriene E4; Lipoxygenase Inhibitors; Muscle, Smooth; Naphthaleneacetic Acids; Oxygen; Quinolines; Rats; Rats, Sprague-Dawley

We determined if pulmonary peptidoleukotrienes contribute to the pathogenesis of chronic lung disease of extreme prematurity (CLD) by measuring urinary leukotriene E4 (uLTE4). Study patients had a birth weight < 1000 g and were about 28 d old when they were classified as normal control subjects (n = 8) or as having CLD (n = 26, abnormal chest X-ray, supplemental O2 requirement +/- ventilator). Urinary LTE4 levels were significantly elevated in CLD compared with the control group (288 +/- 92 versus 35 +/- 10 pg/mg creatinine, mean +/- SE, p < 0.05). Ventilator-dependent CLD patients, who required dexamethasone and had demonstrated uLTE4 levels above the normal range, needed significantly higher peak inspiratory pressures (20 +/- 1 cm H2O versus 15 +/- 1 cm H2O) than similar patients with uLTE4 in the normal range, and the former group had a significant reduction in uLTE4 in the first 5 d of dexamethasone therapy (626 +/- 198 to 451 +/- 176 pg/mg Cr) as ventilatory support was reduced. We conclude that peptidoleukotriene production is activated in patients with CLD (and no other detectable organ dysfunction) to pathophysiologic levels described in adults with acute asthma. Prospective studies focused on infants dependent on high levels of ventilatory support may provide insights into the role of leukotriene synthesis inhibitors or receptor antagonists in the treatment of CLD.

Topics: Bronchopulmonary Dysplasia; Dexamethasone; Humans; Infant, Low Birth Weight; Infant, Newborn; Leukotriene E4; Lung; Respiration, Artificial

The sulphidopeptide leukotrienes (C4, D4, and E4) are potent airway constrictors that have been detected in the airways of infants with pulmonary hypertension and viral infections. The present study was undertaken to test the hypothesis that leukotrienes in tracheal lavage fluid are elevated in bronchopulmonary dysplasia. Twenty-six intubated infants (10 with bronchopulmonary dysplasia, 9 with hyaline membrane disease, and 7 normal controls) had tracheal lavage leukotriene levels determined by radioimmunoassay. Lavage fluid cell counts (alveolar macrophages) and leukotriene levels were significantly increased in infants with severe bronchopulmonary dysplasia. The increased concentration of leukotrienes seen in the infants with bronchopulmonary dysplasia would suggest a possible role for these compounds in the pathophysiology of this disease.

Topics: Bronchopulmonary Dysplasia; Humans; Hyaline Membrane Disease; Infant, Newborn; Leukotriene E4; SRS-A; Therapeutic Irrigation; Trachea