interleukin-8 and Bronchopulmonary-Dysplasia

This study aims to investigate the preventive effects of caffeine citrate on cytokine profile and bronchopulmonary dysplasia (BPD) in preterm infants with apnea.. Preterm infants with apnea who were born at less than 32 weeks of gestational age and birth weight ≤1500 g were randomly divided into caffeine citrate prevention group and caffeine citrate treatment group. Preterm infants in caffeine citrate prevention group who were at risk of developing recurrent apnea were given to caffeine citrate within 8 h after birth. Those in caffeine citrate treatment group experienced apnea after birth were given to caffeine citrate for treatment. Preterm infants in both groups were treated with the same respiratory management and other conventional therapy. After drug discontinuation, levels of cytokine profile, and incidence of BPD were compared between two groups.. A total of 56 preterm infants were enrolled. Differences in gestational age (P=0.11) and birth weight (P=0.251) were not statistically significant. Differences in application time of caffeine citrate (P=0.356), hour of ventilator use (P=0.152), length of stay (P=0.416) and BPD morbidity (P=1.00) between two groups were not statistically significant. At birth, there were no statistically significant in levels of IL-6 (P=0.063) and IL-8 (P=0.125) between two groups. After conventional therapy, levels of IL-6 (P=0.001) and IL-8 (P=0.001) significantly decreased in caffeine citrate prevention group compared with those in caffeine citrate treatment group.. Prevention usage of caffeine citrate in preterm infants with apnea could reduce the level of cytokine profile and the incidence of BPD.

Topics: Apnea; Birth Weight; Bronchopulmonary Dysplasia; Caffeine; Central Nervous System Stimulants; Citrates; Drug Administration Schedule; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Infusions, Intravenous; Interleukin-6; Interleukin-8; Length of Stay; Maintenance Chemotherapy; Male; Respiration, Artificial; Time Factors

We compared serial measurements of inflammatory mediators and markers in infants treated with inhaled nitric oxide or placebo to assess the effects of inhaled nitric oxide therapy on lung inflammation during bronchopulmonary dysplasia. We investigated relationships between respiratory severity scores and airway concentrations of inflammatory markers/mediators.. As part of the Nitric Oxide (to Prevent) Chronic Lung Disease trial, a subset of 99 infants (52 placebo-treated infants and 47 inhaled nitric oxide-treated infants; well matched at baseline) had tracheal aspirate fluid collected at baseline, at 2 to 4 days, and then weekly while still intubated during study gas treatment (minimum of 24 days). Fluid was assessed for interleukin-1beta, interleukin-8, transforming growth factor-beta, N-acetylglucosaminidase, 8-epi-prostaglandin F2alpha, and hyaluronan. Results were normalized to total protein and secretory component of immunoglobulin A.. At baseline, there was substantial variability of each measured substance and no correlation between tracheal aspirate fluid levels of any substance and respiratory severity scores. Inhaled nitric oxide administration did not result in any time-matched significant change for any of the analytes, compared with the placebo-treated group. There was no correlation between any of the measured markers/mediators and respiratory severity scores throughout the 24 days of study gas administration. In the posthoc analysis of data for inhaled nitric oxide-treated infants, there was a difference at baseline in 8-epi-prostaglandin F2alpha levels for infants who did (n = 21) and did not (n = 26) develop bronchopulmonary dysplasia at postmenstrual age of 36 weeks.. Inhaled nitric oxide, as administered in this study, seemed to be safe. Its use was not associated with any increase in airway inflammatory substances.

Topics: Administration, Inhalation; Biomarkers; Bronchopulmonary Dysplasia; Cytokines; Dinoprost; Double-Blind Method; Female; Humans; Infant, Newborn; Infant, Premature; Inflammation Mediators; Interleukin-1beta; Interleukin-8; Male; Nitric Oxide; Prognosis; Reference Values; Reproducibility of Results; Respiration, Artificial; Sensitivity and Specificity; Trachea; Transforming Growth Factor beta; Treatment Outcome

Lung fluid obtained by tracheal aspiration (TA) or bronchoalveolar lavage (BAL) has been used to study bronchopulmonary dysplasia (BPD). These two sample collection methods have seldom been compared. Paired BAL and TA specimens were collected 1, 3, 7 and 28 days after birth in 40 infants <34 weeks' gestation during a randomized, controlled trial of dexamethasone for BPD prophylaxis. Interleukin 8 (IL-8) and cell counts were measured. Compared to subjects without BPD, those who developed BPD or died by 28 days had elevated IL-8 in epithelial lining fluid on day 1 in both BAL specimens (20 ng/ml vs. 2 ng/ml) and TA specimens (101 ng/ml vs. 18 ng/ml). IL-8 levels (r = 0.55) and neutrophil proportions (r = 0.51) were moderately correlated between BAL and TA samples. TA specimens may be suitable substitutes for BAL samples in some studies of newborn lung fluid.

Topics: Body Fluids; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Dexamethasone; Double-Blind Method; Gestational Age; Glucocorticoids; Humans; Infant, Newborn; Infant, Premature; Interleukin-8; Leukocyte Count; Neutrophils; Placebos; Prognosis; Sensitivity and Specificity; Suction; Trachea; Urea

We tested the hypothesis that inhaled beclomethasone therapy for prevention of bronchopulmonary dysplasia (BPD) reduces pulmonary inflammation. As part of a randomized, placebo-controlled trial, interleukin-8 (IL-8) and interleukin-1 receptor antagonist (IL-1ra) concentrations in tracheal aspirates were measured as markers of pulmonary inflammation. On study days 1 (baseline), 8, 15, and day 28 of age, samples were obtained from enrolled infants (birth weights <1,251 g, gestational age <33 week, 3 to 14 days of age) who remained ventilated and had not received systemic glucocorticoid therapy. Cytokine levels (pg/microg of free secretory component of immunoglobulin A) were compared between groups. We determined whether baseline cytokine levels modified treatment effect regarding subsequent need for systemic glucocorticoid therapy or occurrence of BPD (age 28 days). Tracheal aspirates were obtained from 161 infants (77 receiving beclomethasone, 84 receiving placebo). Median IL-8 levels were lower in beclomethasone versus placebo infants on study days 8 (82.9 vs. 209.2, P < 0.01) and 15 (37.4 vs. 77.4, P < 0.03) after controlling for antenatal glucocorticoid therapy and maternal race. Median IL-1ra levels were lower in beclomethasone versus placebo infants only on study day 8 (86.5 vs. 153.3, P < 0.01). Fewer beclomethasone infants with baseline IL-8 levels in the interquartile range required systemic glucocorticoid therapy (beclomethasone 30.6% vs. placebo 65.8%, P < 0.01) or developed BPD (beclomethasone 42.4% vs. placebo 69.4%, P < 0.03). We conclude that early-inhaled beclomethasone therapy was associated with a reduction in pulmonary inflammation after 1 week of therapy. Beclomethasone-treated infants with moderately elevated baseline IL-8 levels received less subsequent systemic glucocorticoid therapy and had a lower incidence of BPD than nontreated infants.

Topics: Administration, Inhalation; Beclomethasone; Body Fluids; Bronchopulmonary Dysplasia; Female; Glucocorticoids; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Inflammation Mediators; Interleukin-8; Male; Receptors, Interleukin-1; Respiration, Artificial; Trachea

Ventilated preterm infants prone to the development of bronchopulmonary dysplasia have been shown to have increased inflammatory mediators in their tracheal aspirates. High frequency oscillatory ventilation (HFOV) is thought to be less traumatic than intermittent positive pressure ventilation (IPPV) in premature infants with surfactant deficiency, and therefore may reduce the inflammatory response in tracheobronchial aspirates. We randomized 76 premature infants requiring mechanical ventilation (birth weight 420-1830 g, median 840 g, gestational age 23 3/7 to 29 2/7 wk, median 26 4/7 to receive either an IPPV with a high rate (60-80/min) and low peak pressures, or an HFOV aiming at an optimization of lung volume, within 1 h of intubation. Tracheal aspirates were systematically collected during the first 10 d of life and analyzed for albumin, IL-8, leukotriene B4 (LTB4), and the secretory component (SC) for IgA as a reference protein. Bacterially colonized samples were excluded. On the treatment d 1, 3, 5, 7, and 10, the resulting median values of albumin (milligrams/mg of SC) were 28, 23, 24, 18, and 10, in IPPV-ventilated infants, and 33, 28, 18, 25, and 39 in HFOV-ventilated infants, respectively. Median IL-8 values (nanograms/mg of SC) were 671, 736, 705, 1362, and 1879 (IPPV) and 874, 1713, 1029, 1426, and 1823 (HFOV), respectively, and median LTB4 values (nanograms/mg of SC) were 26, 13, 27, 22, and 11 (IPPV) and 15, 12, 7, 12, and 16 (HFOV), respectively. Values were similar in IPPV- and HFOV-ventilated infants, and no significant differences were noted. We conclude that HFOV, when compared with a high rate low pressure IPPV, does not reduce concentrations of albumin, IL-8, and LTB4 in tracheal aspirates of preterm infants requiring mechanical ventilation.

Topics: Albumins; Bronchopulmonary Dysplasia; Female; High-Frequency Ventilation; Humans; Immunoglobulin A; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-8; Intermittent Positive-Pressure Ventilation; Leukotriene B4; Lung; Male; Pregnancy

The object of this study was to examine the hypothesis that meter-dosed, inhaled beclomethasone administered to premature infants beginning at birth in a tapering dosage schedule over the first 12 days of life attenuates bronchoalveolar lining fluid oxyradical inflammation concomitant with modulation of bronchopulmonary dysplasia. The design of this study was an unblinded, uncontrolled phase I, pilot investigation of inhaled beclomethasone primarily examining safety and administration. The setting was a tertiary care neonatal intensive care unit. Intubated, premature infants were studied longitudinally to 36 weeks corrected gestational age. Meter-dosed, inhaled beclomethasone was administered in a tapering dosage schedule over the first 12 days of life. Endotracheal tube aspirates were collected on Days 2, 4, and 6 of life and assayed for various markers of bronchoalveolar lining fluid oxyradical stress. Infants were also assessed with regards to a number of relevant clinical variables and presence or absence of bronchopulmonary dysplasia at 36 weeks corrected gestational age. Although no differences in clinical outcome were apparent in comparing nine control infants with nine beclomethasone-treated infants, bronchoalveolar lining fluid from control infants exhibited evidence of apparent phospholipid peroxidation (enhanced polyunsaturated fatty acid consumption) on Day 2 of life compared to beclomethasone-treated infants. Significant differences were noted for percent arachidonic acid, total polyunsaturated fatty acids and ratio of polyunsaturated fatty acids, to saturated fatty acids. The ratio of monohydroxyl linolenic acid to native linoleic acid (a more specific marker of lipid peroxidation) as well as myeloperoxidase activity (a marker of neutrophil oxyradical stress) tended to be higher in the control group but did not achieve statistical significance for this small subject number study. No adverse reactions related to meter-dosed, inhaled beclomethasone were noted in the treatment group; most specifically no evidence of hypothalamic-pituitary-adrenal axis suppression was noted in either control or beclomethasone-treated infants. Meter-dosed, inhaled beclomethasone in the dosage schedule utilized was safe and appeared to moderate bronchoalveolar lining fluid phospholipid peroxidation. Small numbers of infants entered into the present investigation preclude comments on clinical efficacy because of the likelihood of a statistical type 2 error. However

Topics: Administration, Inhalation; Beclomethasone; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Fatty Acids; Female; Gestational Age; Humans; Hypothalamo-Hypophyseal System; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-8; Lipid Peroxidation; Lung Diseases; Male; Nebulizers and Vaporizers; Peroxidase; Phospholipids; Pilot Projects; Pituitary-Adrenal System; Reactive Oxygen Species; Severity of Illness Index

An imbalance of proinflammatory cytokines such as TNF-alpha, IL-1 beta, and the neutrophil chemotactic factor IL-8 and inhibitors (e.g., soluble TNF receptors and IL-1ra) in the lung during the first week of life may contribute to prolonged pulmonary inflammation and fibrosis in bronchopulmonary dysplasia (BPD). Disodium cromoglycate (DSCG) has anti-inflammatory effects in asthma, a disease with many similarities with BPD. In a prospective, randomized, blinded study, we examined whether early DSCG therapy inhibits proinflammatory cytokines in infants at risk for BPD. Twenty-six infants who were identified as high risk (> or = 75% probability) for oxygen-dependency at 28 d by a 12-h predictive score and survived 48 h were randomized to nebulized DSCG 20 mg (n = 13) or 2 cc NS (control, n = 13) every 6 h from Day 3 to Day 28. Lung lavage was collected on Day 3 (pre-study) and Day 7 and analyzed for cell count and differential and TNF-alpha, sTNFR1, sTNFR2, IL-1 beta, IL-1ra, and IL-8 concentrations. The groups' pre-study lavage cytokine concentrations were similar, but TNF-alpha and IL-8 concentrations were 3.6- and 4.9-fold lower in the DSCG group on Day 7 compared with levels in the control group. Soluble TNF receptors were unaffected by DSCG. There was a trend towards lower IL-1 beta levels in DSCG-treated infants on Day 7, but IL-1ra levels were unaffected by DSCG therapy. Three control subjects, but no DSCG-treated infants, died during the study period (p = 0.07). There were no significant differences between survivors of the two groups for oxygen-dependency at 28 d (100% control subjects; 85% DSCG). These results suggest that nebulized DSCG may exert an anti-inflammatory effect in the lungs of infants < or = 1,000 g at risk for BPD.

Topics: Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Cell Count; Cromolyn Sodium; Cytokines; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Humans; Infant, Newborn; Inflammation Mediators; Interleukin-1; Interleukin-8; Macrophages; Neutrophils; Prospective Studies; Risk Factors; Tumor Necrosis Factor-alpha

The role of prematurity and pulmonary inflammation in the pathogenesis of bronchopulmonary dysplasia (BPD) is very well-defined. However, there is limited knowledge about whether the level of prematurity and surfactant therapy alter the pulmonary cytokines and endothelial growth factor (VEGF).. This study analyzed the VEGF and cytokines, including interleukin (IL)-1β, IL-6, IL-8, and IL-10, and tumor necrosis factor α (TNF-α) in the tracheal aspirate (TA) of preterm infants obtained before (within 2 h after birth) and 10-12 h after the administration of the first dose of surfactant. TA was collected from 40 infants of 35 or fewer weeks of gestation, including extremely (Group 1, n = 19), very (Group 2, n = 13), and moderate/late (Group 2, n = 8) preterm neonates. In addition to univariate analysis, controlled regression models estimated the association of perinatal factors with the tested parameters and their role in the development of BPD.. We recorded significantly lower post-partum levels of VEGF and higher IL-8, IL-1β, and TNF-α in the TA of Group 1 infants than in Group 2 and 3. Compared to the infants in Group 2 and 3, the post-surfactant increases of pulmonary VEGF, IL-8, IL-10, and TNF-α were more significant in Group 1. All tested parameters in Group 1 and 2 infants, before and after surfactant administration, were comparable. BPD was recorded in nearly 60% of the extremely preterm survivors and was significantly predicted by increased IL-8 before, and elevated TNF-α level after surfactant administration.. This study indicates the association of birth at extremely preterm gestation with reduction in pulmonary VEGF and exacerbation of pro-inflammatory cytokines followed by greater elevation post-surfactant administration levels of VEGF, IL-8, TNF-α, and IL-10 than in neonates born with gestational age of 28-35 weeks.

Topics: Bronchopulmonary Dysplasia; Cytokines; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Inflammation Mediators; Interleukin-10; Interleukin-8; Pneumonia; Pregnancy; Pulmonary Surfactants; Surface-Active Agents; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

To measure plasma levels of vascular endothelial growth factor (VEGF) and several cytokines (Interleukin [IL]-6 IL-8, IL-10) during the first week of life to examine the relationship between protein expression and likelihood of developing respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD).. Levels of IL-6, IL-8, IL-10, and VEGF were measured from plasma obtained from preterm patients during the first week of life. Newborns were recruited from a single center between April 2009 and April 2019. Criteria for the study included being inborn, birth weight of less than 1500 grams, and a gestational age of less than 32 weeks at birth.. The development of RDS in preterm newborns was associated with lower levels of VEGF during the first week of life. Higher plasma levels of IL-6 and IL-8 plasma were associated with an increased likelihood and increased severity of BPD at 36 weeks postmenstrual age. In contrast, plasma levels of VEGF, IL-6, IL-8, and IL-10 obtained during the first week of life were not associated with respiratory symptoms and acute care use in young children with BPD in the outpatient setting.. During the first week of life, lower plasma levels of VEGF was associated with the diagnosis of RDS in preterm infants. Preterm infants with higher levels of IL-6 and IL-8 during the first week of life were also more likely to be diagnosed with BPD. These biomarkers may help to predict respiratory morbidities in preterm newborns during their initial hospitalization.

Topics: Biomarkers; Bronchopulmonary Dysplasia; Cytokines; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Interleukin-10; Interleukin-6; Interleukin-8; Pregnancy; Respiratory Distress Syndrome, Newborn; Vascular Endothelial Growth Factor A

Bronchopulmonary dysplasia (BPD) is an abnormality that occurs in premature neonate lung development. The pathophysiology is uncertain, but the inflammatory response to lung injury may be the responsible pathway. The objective of this study is to evaluate the role of interleukins 6, 8, 10, and 17 through the anatomopathological and immunohistochemical study of the lungs of premature neonates with BPD. Thirty-two cases of neonatal autopsies from the Pathology Department of the Clinics Hospital of the Universidade Federal do Paraná, who presented between 1991 and 2005 were selected. The sample included neonates less than 34 weeks of gestational age who underwent oxygen therapy and had pulmonary formalin-fixed paraffin-embedded (FFPE) samples. Pulmonary specimens were later classified into three groups according to histopathological and morphometric changes (classic BPD, new BPD, and without BPD) and subjected to immunohistochemical analysis. The antibodies selected for the study were anti-IL-6, anti-IL-8, anti-IL-10, and anti-IL-17A monoclonal antibodies. IL-6, IL-8, and IL-10 showed no significant differences in tissue expression among the groups. IL-17A had higher tissue immunoreactivity in the group without BPD compared with the classic BPD group (1686 vs. 866 μm

Topics: Bronchopulmonary Dysplasia; Female; Humans; Infant, Newborn; Infant, Premature; Interleukin-10; Interleukin-17; Interleukin-6; Interleukin-8; Interleukins; Lung; Male

The aim of this study was to investigate the role of pre-B cell colony-enhancing factor (PBEF) in the pathogenesis of bronchopulmonary dysplasia (BPD) using an established cell model of BPD. For this purpose, EA.hy926 cell cultures were divided into 4 groups as follows: the air group as the blank control, the hyperoxia group, the hyperoxia plus PBEF siRNA group and the hyperoxia plus scramble siRNA group. Cell viability and the generation of reactive oxygen species (ROS) were determined using respective kits. Moreover, the protein and mRNA expression levels of PBEF, interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) were also detected by corresponding methods. Compared with the hyperoxia group, the ROS levels in the hyperoxia plus PBEF siRNA group were significantly reduced (P<0.01). The silencing of PBEF increased cell viability compared with the hyperoxia group. The protein and mRNA expression levels of PBEF, IL-8 and TNF-α were all decreased in the hyperoxia plus PBEF siRNA group compared with the hyperoxia group (P<0.01). Our study thus demonstrates that the inhibition of PBEF attenuates oxidative stress and inflammation induced by hyperoxia in EA.hy926 cells, suggesting that PBEF may be a potential diagnostic and therapeutic target, which may be used for the development of novel treatment strategies for BPD.

Topics: Bronchopulmonary Dysplasia; Cell Line; Cytokines; Humans; Hyperoxia; Inflammation; Interleukin-8; Nicotinamide Phosphoribosyltransferase; Oxidative Stress; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

Although oxidative stress and inflammation are important mechanisms in the pathophysiology of preeclampsia and preterm diseases, their contribution to the respiratory prognosis of premature infants of hypertensive mothers is not known. Our objective was to determine the levels of oxidative stress and inflammation markers in the airways of premature infants born to hypertensive and normotensive mothers, in the first 72 h of life, and to investigate whether they are predictors of bronchopulmonary dysplasia (BPD)/death. This was a prospective study with premature infants less than 34 weeks' gestation on respiratory support who were stratified into 2 groups: 32 premature infants of hypertensive mothers and 41 of normotensive women, with a mean gestational age of 29 weeks. Exclusion criteria were as follows: diabetes mellitus, chorioamnionitis, malformation, congenital infection, and death within 24 h after birth. The outcome of interest was BPD/death. Malondialdehyde (MDA), nitric oxide (NO), and interleukin 8 (IL-8) were measured in airway aspirates from the first and third days of life and did not differ between the groups. Univariate and multivariate statistical analyses were performed. The concentrations of MDA, NO, and IL-8 were not predictors of BPD/death. Premature infants who developed BPD/death had higher levels of IL-8 in the first days of life. The gestational age, mechanical ventilation, and a small size for gestational age were risk factors for BPD/death. In conclusion, the biomarkers evaluated were not increased in premature infants of hypertensive mothers and were not predictors of BPD/death.

Topics: Biomarkers; Bronchopulmonary Dysplasia; Female; Humans; Hypertension, Pregnancy-Induced; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-8; Longitudinal Studies; Malondialdehyde; Nitric Oxide; Oxidative Stress; Predictive Value of Tests; Prospective Studies

Airway inflammation is involved in the pathogenesis of bronchopulmonary dysplasia (BPD). The aim of the study was to evaluate the inflammatory activity in plasma and exhaled air in very low birth weight (VLBW) BPD survivors at school age.. Twenty-one 6-14-year-old former VLBW (birth weight ≤1,500 g) children with severe radiographic BPD (radBPD), 19 without radBPD (nonBPD group) and 19 non-asthmatic term controls underwent measurement of eosinophil cationic protein, IL-6, IL-8, adiponectin, adipsin, leptin, and resistin in plasma, leukotriene B4 and 8-isoprostane in exhaled breath condensate, and NO in exhaled breath. Background data were obtained from patient records, clinical examination and parental questionnaire. Both univariate and multivariate models were applied in the statistical analysis.. There were no significant differences between the groups in any of the inflammatory markers measured. Five (25%) radBPD and 2 (11%) nonBPD children reported asthma (P = 0.058). In logistic regression analysis, exposure to chorioamnionitis was associated with low IL-8 (OR 29.0, 95% CI 3.27-258) and postnatal corticosteroid therapy with high adiponectin (OR 32.0, 95% CI 1.29-793). High body mass index standard deviation score (BMI-SDS) was associated with high plasma adipsin (OR 2.47, 95% CI 1.07-5.75) and leptin (OR 5.76, 95%CI 1.83-18.2) levels.. The inflammatory activity seems to decrease by school age in VLBW BPD survivors. Chorioamnionitis and postnatal corticosteroid treatment may modulate the inflammatory responsiveness in VLBW subjects even up to school age. The respiratory outcome in VLBW infants might be improved by preventing excessive weight gain.

Topics: Adiponectin; Adolescent; Asthma; Biomarkers; Body Mass Index; Bronchopulmonary Dysplasia; Child; Chorioamnionitis; Complement Factor D; Female; Finland; Glucocorticoids; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Interleukin-6; Interleukin-8; Leptin; Logistic Models; Pregnancy; Survivors

To determine whether specific macrophage immune functions of the newly born are insensitive to the actions of therapeutic levels of dexamethasone (DEX), previously measured in infants with bronchopulmonary dysplasia (BPD), compared with betamethasone (BETA) and exogenous or endogenous interleukin-10 (IL-10).. Macrophages were differentiated from cord blood monocytes (N=18). A serial dose-response (around 10(-8 )M), in vitro study was used to examine the effect of DEX, BETA and IL-10, on proinflammatory (PI) cytokine release, phagocytosis and respiratory burst.. Exogenous IL-10 (10(-8 )M) significantly (P<0.05) inhibited the endotoxin-stimulated release of IL-6, IL-8 and tumor necrosis factor by 63 to 82% with no significant effect by DEX and BETA. There was no inhibition by these three agents at 10(-8 )M on phagocytosis and respiratory burst. Inhibition of endogenous IL-10 with a monoclonal antibody significantly increased endotoxin-stimulated cytokine release by at least fourfold.. Macrophages were relatively insensitive to therapeutic levels of DEX and BETA with regard to PI cytokine release. This study provides rationale for translational and preclinical research using airway instillation of IL-10 for the treatment of BPD.

Topics: Betamethasone; Bronchopulmonary Dysplasia; Dexamethasone; Glucocorticoids; Humans; Infant, Newborn; Interleukin-10; Interleukin-6; Interleukin-8; Macrophages; Phagocytosis; Respiratory Burst; Tumor Necrosis Factor-alpha

The chemokine interleukin-8 is implicated in the development of bronchopulmonary dysplasia in preterm infants. The 77-amino acid isoform of interleukin-8 (interleukin-877) is a less potent chemoattractant than other shorter isoforms. Although interleukin-877 is abundant in the preterm circulation, its regulation in the preterm lung is unknown.. To study expression and processing of pulmonary interleukin-877 in preterm infants who did and did not develop bronchopulmonary dysplasia.. Total interleukin-8 and interleukin-877 were measured in bronchoalveolar lavage fluid from preterm infants by immunoassay. Neutrophil serine proteases were used to assess processing. Neutrophil chemotaxis assays and degranulation of neutrophil matrix metalloproteinase-9 were used to assess interleukin-8 function.. Peak total interleukin-8 and interleukin-877 concentrations were increased in infants who developed bronchopulmonary dysplasia compared to those who did not. Shorter forms of interleukin-8 predominated in the preterm lung (96.3% No-bronchopulmonary dysplasia vs 97.1% bronchopulmonary dysplasia, p>0.05). Preterm bronchoalveolar lavage fluid significantly converted exogenously added interleukin-877 to shorter isoforms (p<0.001). Conversion was greater in bronchopulmonary dysplasia infants (p<0.05). This conversion was inhibited by α-1 antitrypsin and antithrombin III (p<0.01). Purified neutrophil serine proteases efficiently converted interleukin-877 to shorter isoforms in a time- and dose-dependent fashion; shorter interleukin-8 isoforms were primarily responsible for neutrophil chemotaxis (p<0.001). Conversion by proteinase-3 resulted in significantly increased interleukin-8 activity in vitro (p<0.01).. Shorter, potent, isoforms interleukin-8 predominate in the preterm lung, and are increased in infants developing bronchopulmonary dysplasia, due to conversion of interleukin-877 by neutrophil serine proteases and thrombin. Processing of interleukin-8 provides an attractive therapeutic target to prevent development of bronchopulmonary dysplasia.

Topics: Bronchopulmonary Dysplasia; Cells, Cultured; Chemotaxis; Humans; Infant; Infant, Newborn; Infant, Premature; Interleukin-8; Neutrophils; Respiration, Artificial; Serine Proteases

Various cytokines have been associated to the occurrence of bronchopulmonary dysplasia (BPD) in preterm neonates.. To establish an association between cord blood cytokines and BPD, so that they could be used, in clinical practice, as early markers of BPD.. Preterms less than 30 weeks gestational age, were analysed by ELISA microassay for venous cord blood IL-1β, IL-6, IL-8, TNF-α and IL-10, and compared between the BPD and non-BPD groups.. One hundred and fifty neonates completed the study; 31 (21%) small for gestational age (SGA); 16 were deceased before 28 days of life; 36 developed mild BPD and 20 developed moderate/severe BPD. Elevated cord blood IL-8 was associated with death or moderate/severe BPD. SGA patients with moderate/severe BPD presented higher cord blood values of IL-8, lower IL-6 and IL-10 when compared with SGA without moderate/severe BPD; and higher IL-8 levels when compared with patients without moderate/severe BPD.. These results support an association between cord blood IL-8 and moderate/severe BPD, independently of the intra-uterine growth; and the association of cord blood IL-6 and IL-10 and moderate/severe BPD in SGA preterm newborns.

Topics: Biomarkers; Bronchopulmonary Dysplasia; Early Diagnosis; Female; Fetal Blood; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Small for Gestational Age; Interleukin-10; Interleukin-6; Interleukin-8; Male; Tumor Necrosis Factor-alpha

The role of granulocyte-specific S100A12, a marker for inflammatory disorders, in newborn lung disease is unknown. We compared postnatal blood S100A12 concentrations against respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD).. Blood samples from 92 newborns were collected on admission, 12 h, day 1, day 3-4 and day 7, and analysed for S100A12. IL-8 and IL-6 were assayed in 52 infants.. Infants with RDS were significantly more premature (median 27 vs. 34 weeks), more likely to receive antenatal corticosteroids (84% vs. 26%) and have lower neutrophil counts (median 2.4 vs. 3.8 × 10(9) /L) at admission. S100A12 levels peaked during the first day and were significantly lower in preterm infants with RDS compared to those without (median 250 vs. 616 ng/mL at 12 h, 281 vs. 828 ng/mL day 1, respectively). S100A12 levels were low among the 35 very preterm infants (24-29 week gestation) regardless of the presence of BPD (285 vs. 288 ng/mL on day 1). In comparison, IL-8 and IL-6 levels were not different between groups.. Plasma S100A12 is low in infants with RDS, possibly because of gestationally related differences in neutrophil response or to the effects of antenatal corticosteroids. It is therefore not a useful marker of BPD development.

Topics: Biomarkers; Bronchopulmonary Dysplasia; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Interleukin-6; Interleukin-8; Leukocyte Count; Logistic Models; Neutrophils; Respiratory Distress Syndrome, Newborn; S100 Proteins; S100A12 Protein

To investigate the expression of interleukin 8 (IL-8), surfactant protein-A (SP-A) and transforming growth factor beta1 (TGF-beta1) in bronchoalveolar lavage fluid (BALF) of neonates with bronchopulmonary dysplasia (BPD).. Thirty neonates with BPD and 30 gestational age-, gender-, and birth weight-matched neonates without BPD (control group) were enrolled from December 2007 to October 2009. Non-brochoscopic bronchoalveolar lavage was performed. The levels of IL-8, SP-A and TGF-beta1 in BALF were measured using ELISA.. The levels of TGF beta1 (47+/-15 microg/mL vs 34+/-13 microg/mL) and IL-8 (54+/-16 microg/mL vs 28+/-13 microg/mL) in the BPD group were significantly higher than those in the control group (P<0.01). In contrast, the contents of SP-A in the BPD group were significantly lower than those in the control group (35+/-16 microg/mL vs 42+/-14 microg/mL;P<0.05).. The increased expression of TGF-beta1 and IL-8 in BALF may be involved in abnormal lung development and maturation in neonates with BPD. The low expression of SP-A in the BPD group suggests that the exogenous SP-A administration may be an option for the treatment of BPD.

Topics: Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant, Newborn; Interleukin-8; Male; Pulmonary Surfactant-Associated Protein A; Transforming Growth Factor beta1

To evaluate the influence of chorioamnionitis (CA) on plasma cytokines and the cytokine-associated risk of bronchopulmonary dysplasia (BPD) during the perinatal period.. Eleven cytokines from 128 very low gestational age infants were analyzed from cord blood and from plasma at ages 1 day and 7 days after birth. The diagnosis of CA was based on histology of the placenta, fetal membranes, and umbilical cord. Neonatal risk factors were recorded.. In the 48 infants born with CA, high concentrations of inflammatory cytokines in cord blood decreased during the first postnatal day. Inflammatory cytokines in cord blood was associated with the severity of CA. At 1 day after birth, the concentration of interleukin (IL)-8 predicted the risk of BPD. For the 75 infants born without CA, cytokine concentrations increased after birth. For the 128 infants born with or without CA, at 1 day after birth, the concentrations of IL-8, granulocyte colony-stimulating factor, and anti-inflammatory IL-10 were associated with the risk of BPD, after adjustment for the duration of gestation and severity of respiratory distress during the first day.. In infants exposed to CA, insufficient inhibition of high fetal inflammatory cytokine response shortly after birth may increase the risk of BPD.

Topics: Adult; Bronchopulmonary Dysplasia; Chorioamnionitis; Cytokines; Female; Fetal Blood; Humans; Infant, Newborn; Infant, Premature; Interleukin-10; Interleukin-8; Male; Pregnancy; Prospective Studies; Risk Factors; ROC Curve; Sensitivity and Specificity

The goal was to develop multivariate logistic regression models for the outcome of bronchopulmonary dysplasia and/or death at postmenstrual age of 36 weeks by using clinical and cytokine data from the first 28 days.. For 1067 extremely low birth weight infants in the Neonatal Research Network of the National Institute of Child Health and Human Development, levels of 25 cytokines were measured in blood collected within 4 hours after birth and on days 3, 7, 14, and 21. Stepwise regression analyses using peak levels of the 25 cytokines and 15 clinical variables identified variables associated with bronchopulmonary dysplasia/death. Multivariate logistic regression analysis was performed for bronchopulmonary dysplasia/death by using variables selected through stepwise regression. Similar analyses were performed by using average cytokine values from days 0 to 21, days 0 to 3, and days 14 to 21.. Of 1062 infants with available data, 606 infants developed bronchopulmonary dysplasia or died. On the basis of results from all models combined, bronchopulmonary dysplasia/death was associated with higher concentrations of interleukin 1beta, 6, 8, and 10 and interferon gamma and lower concentrations of interleukin 17, regulated on activation, normal T cell expressed and secreted, and tumor necrosis factor beta. Compared with models with only clinical variables, the addition of cytokine data improved predictive ability by a statistically significant but clinically modest magnitude.. The overall cytokine pattern suggests that bronchopulmonary dysplasia/death may be associated with impairment in the transition from the innate immune response mediated by neutrophils to the adaptive immune response mediated by T lymphocytes.

Topics: Bronchopulmonary Dysplasia; Chorioamnionitis; Cytokines; Female; Humans; Immunity, Cellular; Immunity, Innate; Infant, Extremely Low Birth Weight; Infant, Newborn; Interferon-gamma; Interleukin-1beta; Interleukin-6; Interleukin-8; Logistic Models; Male; Multivariate Analysis; Pregnancy

Cytokine profiles in amniotic fluid, cord serum, and tracheal aspirate of premature infants suggest a shift toward a proinflammatory state. Cytokines also contribute to the pathogenesis of bronchopulmonary dysplasia (BPD). We hypothesize that the initiating events for BPD are reflected in the placenta and propose that placental expression of cytokines provide a blueprint of events leading to BPD. This is a retrospective, case-controlled study of placental cytokines of premature infants with (n = 49) and without (n = 49) BPD, matched for gender, birth weight, and year of birth at Women and Infants Hospital between 2003 and 2005. Cytokine expression, including IL-6 and IL-10, was determined by immunohistochemistry in membrane rolls, umbilical cords, and placentas. IL-6 was similarly expressed in all tissues of infants with and without BPD. In contrast, anti-inflammatory cytokine IL-10 was less prominent in the placenta of patients with BPD compared with those without BPD. IL-10 expression in the villous trophoblast layer was associated with a reduced odds ratio of developing BPD (adjusted OR 0.08, 95% CI 0.01-0.70, p = 0.02). These results suggest that a placental balance between inflammatory and anti-inflammatory cytokines is crucial to normal lung organogenesis. Importantly, IL-10 seems to be protective against the development of BPD.

Topics: Bronchopulmonary Dysplasia; Case-Control Studies; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Interleukin-10; Interleukin-6; Interleukin-8; Lung; Male; Placenta; Pregnancy; Retrospective Studies; Tumor Necrosis Factor-alpha

All-trans retinoic acid (RA) is a potent modulator of lung development. Chorioamnionitis, which is frequently associated with preterm birth, causes fetal lung inflammation and improves lung function but also results in alveolar simplification and microvascular injury. Endotoxin-mediated chorioamnionitis reduces RA concentration in the fetal lung to 16% of control values. We hypothesized that administration of RA to the fetus before induction of chorioamnionitis would preserve septation of the distal airspaces. Time-mated ewes with singletons were assigned to receive a fetal intramuscular treatment with 20,000 IU of RA in olive oil (or olive oil only) 3 hr prior to intra-amniotic injection of endotoxin (20 mg, E. coli 055:B5) or saline, at 124-day gestational age and 7 days after the fetal treatment. The right cranial lung lobe was processed for morphometric analysis. RA treatment did not affect chorioamnionitis-induced fetal and systemic inflammation or interleukin-8 concentrations in lung tissue. RA administration alone did not alter lung structure. Relative to control lungs (5 +/- 3 mL/kg), lung volume increased similarly with endotoxin (22 +/- 4 mL/kg) or RA plus endotoxin (20 +/- 3 mL/kg; P < 0.05). Alveolar wall thickness was 4.2 +/- 0.3 mum after endotoxin-induced chorioamnionitis, 6.0 +/- 0.4 mum in controls (P < 0.05 versus endotoxin) and 5.5 +/- 0.2 mum after RA and endotoxin (P < 0.05 versus control, n.s. versus endotoxin). The ratio of airspace versus tissue was 4.6 +/- 0.3 in endotoxin-induced chorioamnionitis, 2.1 +/- 0.3 in controls and 4.1 +/- 0.5 after RA and endotoxin. We conclude that fetal treatment with RA did not prevent inflammation-induced alveolar simplification.

Topics: Animals; Bronchopulmonary Dysplasia; Chorioamnionitis; Disease Models, Animal; Elastin; Endotoxins; Female; Fetus; Humans; Infant, Newborn; Interleukin-8; Lung; Pregnancy; Pulmonary Alveoli; Sheep; Tretinoin

Chorioamnionitis is a risk factor for the development of bronchopulmonary dysplasia. Endotoxin-induced oxidative stress to the fetus in the uniquely hypoxic intrauterine environment has not been reported. Using a model of chorioamnionitis, we measured markers of pulmonary and systemic oxidant exposures in fetal lambs at 124 d gestation (term = 150 d) exposed to 10 mg intra-amniotic endotoxin 2 d (n = 6) or 7 d (n = 6) before delivery, or saline as controls (n = 9). The 7 d endotoxin-exposed animals had 3-fold higher protein carbonyls (0.66 +/- 0.46 versus 0.23 +/- 0.14 nmol/mg protein) and 10-fold greater myeloperoxidase activity (2.38 +/- 1.87 versus 0.27 +/- 0.18 nM) in the bronchoalveolar lavage fluid (BALF), suggestive of neutrophil-derived oxidant activity. However, in the lung tissue, protein carbonyls, superoxide dismutase, and peroxiredoxin 1 were not different between groups. The expression of peroxiredoxin 1 was prominent, primarily in the peri-bronchiolar epithelium. Notably, evidence of oxidant exposure was minimal at 2 d when BALF inflammatory cells, lung IL-1beta, and IL-8 were highest. Intra-amniotic endotoxin induced systemic oxidative stress as plasma protein carbonyl was elevated at 7 d (0.14 +/- 0.04 nmol/mg protein; p = 0.005). Surfactant protein A and B mRNAs were highest at 2 d, suggesting that oxidative stress did not contribute to the lung maturation response. A modest lung oxidative stress in chorioamnionitis could contribute to bronchopulmonary dysplasia.

Topics: Amniotic Fluid; Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Chorioamnionitis; Disease Models, Animal; Female; Fetal Organ Maturity; Gestational Age; Humans; Infant, Newborn; Injections; Interleukin-1beta; Interleukin-8; Lipopolysaccharides; Lung; Oxidative Stress; Peroxidase; Peroxiredoxins; Pregnancy; Protein Carbonylation; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein B; RNA, Messenger; Sheep; Superoxide Dismutase; Time Factors

Expression of IL-10 is decreased in lungs of preterm infants. We determined the constitutive and lipopolysaccharide (LPS)-induced IL-10 synthesis by lung inflammatory cells from preterm and term infants and examined their relationship to gestational age and/or incidence of bronchopulmonary dysplasia (BPD). A total of 37 infants; preterm neonates at gestational ages of 23-27 wk (group 1); 28-34 wk (group 2), and four full-term infants with meconium aspiration (group 3) were enrolled. One sample of lung inflammatory cells, obtained during postnatal d 1-3, and another during postnatal d 4-7 were cultured in vitro in presence or absence of 100 mug/mL of LPS. Secreted IL-10 was measured by ELISA. A positive relationship was found between gestational age and LPS-induced, but not constitutive IL-10 production within 1-3 d of life; group 1 on d 1-3 had a significant number of IL-10 nonresponders compared with group 2. All term neonates in group 3 had positive LPS-induced IL-10 response. Thus, in utero maturation of IL-10 gene expression is due to acquisition of inducibility. In contrast, constitutive IL-10 production within d 1-3 of life correlated with, and predicted the incidence of BPD in the highly vulnerable very premature infants.

Topics: Bronchopulmonary Dysplasia; Cells, Cultured; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Interleukin-10; Interleukin-8; Lipopolysaccharides; Lung; Male; Pneumonia; Prospective Studies; Risk Factors

We investigated the relation between perinatal endotracheal colonization, the associated cytokine response and respiratory outcome in ventilated preterm neonates. Between September 1999 and March 2002, a cohort of 141 neonates with a gestational age <31 weeks requiring ventilation directly after birth, were followed prospectively. All were admitted to the Neonatal Intensive Care Unit, University Hospital of Antwerp, Belgium. A tracheal aspirate (TA) sample was collected soon after birth and was processed for microbiological examination, leukocyte count, and cytokine analysis (interleukins [IL] IL-1beta, IL-6, CXCL8 (formerly called IL-8), IL-10, IL-12p70 and tumor necrosis factor alpha [TNF-alpha]). Together with the prospectively registered patient's comorbidities and severity of disease, these inflammatory parameters were analyzed in a multivariate Cox proportional hazards model with time of extubation and duration of oxygen therapy as main outcome measures. Of the 141 patients included, 31 (22%) died before discharge from the unit and 37 (26%) had a positive TA culture. Independent predictors of duration of mechanical ventilation were: gestational age <28 weeks, degree of respiratory distress syndrome (RDS) at birth, significant patent ductus arteriosus (PDA), the SNAP-score, and high levels of CXCL8 (>4,153 pg/ml) in TA only in neonates with a gestational age <28 weeks. Variables associated with extended duration of oxygen therapy were gestational age <28 weeks, birth weight <1,000 g, degree of RDS at birth, and duration of mechanical ventilation.

Topics: Body Fluids; Bronchopulmonary Dysplasia; Cytokines; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Interleukin-8; Leukocyte Count; Prognosis; Prospective Studies; Respiratory Distress Syndrome, Newborn; Risk Factors; Trachea

Nuclear factor-kappaB (NF-kappaB) plays a central role in regulating key proinflammatory mediators. The activation of NF-kappaB is increased in tracheal aspirate (TA) cells from premature infants developing bronchopulmonary dysplasia (BPD). We studied the effect of azithromycin (AZM) on the suppression of NF-kappaB activation and the synthesis of pro-inflammatory cytokines IL-6 and IL-8 by TA cells obtained from premature infants. Tracheal aspirate cells were stimulated with tumor necrosis factor-alpha (TNF-alpha) and incubated with AZM. The nuclear NF-kappaB-DNA binding activity, the levels of inhibitory kappaB-alpha (IkappaB-alpha) in the cytoplasmic fraction and IL-6 and IL-8 release in the cell culture media were measured. Stimulation of TA cells by TNF-alpha increased the activation of NF-kappaB, which was suppressed by the addition of AZM. Increased activation of NF-kappaB was also associated with increased levels of pro-inflammatory cytokines (IL-6 and IL-8). AZM significantly reduced the IL-6 and IL-8 production to the levels similar to control. TNF-alpha stimulation also increased the degradation of IkappaB-alpha, which was restored with the addition of AZM. Our data suggest that AZM therapy may be an effective alternative to steroids in reducing lung inflammation and prevention of BPD in ventilated premature infants.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchopulmonary Dysplasia; Cell Count; Cells, Cultured; Dose-Response Relationship, Drug; Female; Gestational Age; Humans; I-kappa B Proteins; Infant, Newborn; Infant, Premature; Interleukin-6; Interleukin-8; Male; NF-kappa B; NF-KappaB Inhibitor alpha; Respiration, Artificial; Suction; Trachea; Tumor Necrosis Factor-alpha

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.. 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.. Level III university hospital neonatal intensive care unit.. 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.. Tracheal effluent NF-kappaB, IL8, and cell counts, corrected for dilution by secretory component measurement.. 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).. 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.

Topics: Biomarkers; Birth Weight; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Interleukin-8; Intubation, Intratracheal; Leukocyte Count; NF-kappa B; Oxygen Inhalation Therapy; Pneumonia; Prognosis; Trachea

Improved survival because of advances in neonatal care has resulted in an increased number of infants at risk for chronic lung disease. Even though the etiology of lung injury is multifactorial, recent animal and clinical data indicate that pulmonary damage depends in large part on the ventilatory strategies used. Ventilator-associated lung injury was believed to result from the use of high pressure, thus, the term barotraumas. This trauma is believed to involve free-radical damage. Oxidant injury is a serious cause of lung injury. In the present study, 110 newborns with respiratory distress syndrome were studied; 55 were treated with melatonin and the other 55 with placebo. All the subjects were mechanically ventilated with or without guaranteed volume. Proinflammatory cytokines [interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha] were measured in tracheobronchial aspirate and the clinical outcome was evaluated. Melatonin treatment reduced the proinflammatory cytokines and improved the clinical outcome. The beneficial action of melatonin presumably related to its antioxidative actions.

Topics: Bronchopulmonary Dysplasia; Cytokines; Humans; Infant, Newborn; Interleukin-8; Melatonin; Oxygen; Positive-Pressure Respiration; Pulmonary Ventilation; Respiration, Artificial; Tumor Necrosis Factor-alpha

Previously, we have reported marked pulmonary inflammation in infants who develop chronic lung disease of prematurity. We revisited these infants who did not have clinical or laboratory evidence of infection and searched for Ureaplasma urealyticum, group B streptococci, and other microbes by reverse transcription-PCR performed on RNA extracted from 93 bronchoalveolar lavage samples. From infants ventilated for respiratory distress syndrome, 6 (gestation, 28 wk; birthweight, 880 g) were positive for U. urealyticum and 11 (25 wk, 800 g) were negative. Five (83%) positive and four (36%) negative infants developed chronic lung disease. Each infant was colonized with either biovar 1 or biovar 2 but not both. U. urealyticum was very weakly detectable in two infants on d 1 but was detected in five of six infants at d 10. Furthermore, pulmonary neutrophils, alveolar macrophages, soluble intercellular adhesion molecule-1, and IL-1beta on d 10 and IL-6 and IL-8 at d 1 were significantly increased in the positive group. A variety of organisms were identified in six samples between 14 and 21 d of age, but all samples were negative for group B streptococci. Our data suggest that U. urealyticum colonization is associated with the development of pulmonary inflammation in infants who subsequently develop chronic lung disease.

Topics: Acute Disease; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Chronic Disease; Humans; Infant, Newborn; Infant, Premature; Interleukin-1; Interleukin-6; Interleukin-8; Pneumonia; Risk Factors; RNA, Bacterial; RNA, Ribosomal; Ureaplasma Infections; Ureaplasma urealyticum

Preterm delivery is frequently preceded by chorioamnionitis, resulting in exposure of the fetal lung to inflammation. We hypothesized that ventilation of the antenatally inflamed lung would result in amplification of the lung injury. Therefore, we induced fetal lung inflammation with intra-amniotic endotoxin (10 mg of Escherichia coli 055:B5) 4 days before premature delivery at 130 days of gestation. Lung function and lung inflammation after surfactant treatment and 4 h of mechanical ventilation were evaluated. Inflammatory cell numbers in amniotic fluid were increased >10-fold by antenatal endotoxin exposure. Antenatal endotoxin exposure had minimal effects on blood pressure, heart rate, lung compliance, and blood gas values. The endotoxin-exposed lungs required higher ventilation pressures. Ventilation did not increase the number of inflammatory cells or the protein in bronchoalveolar lavage fluid of the endotoxin-exposed animals above that measured in endotoxin-exposed fetuses that were not ventilated. IL-1beta, IL-6, and IL-8 mRNA in cells from bronchoalveolar lavage fluid were increased by antenatal endotoxin exposure but not changed by ventilation. IL-1beta and IL-8 protein was increased in lung tissue by 4 h of ventilation. Very little inflammation was induced by ventilation in this premature lamb model of surfactant treatment and gentle ventilation. After lung inflammation was induced by intra-amniotic endotoxin injection, ventilation did not increase lung injury.

Topics: Animals; Biomarkers; Birth Weight; Bronchopulmonary Dysplasia; Chorioamnionitis; Endotoxins; Female; Humans; Infant, Newborn; Interleukin-1; Interleukin-6; Interleukin-8; Obstetric Labor, Premature; Pneumonia; Pregnancy; Respiration, Artificial; RNA, Messenger; Sheep

Current nonhuman models for bronchopulmonary dysplasia have not included perinatal infection. We studied the effects of antenatal Ureaplasma urealyticum (Uu) infection in the 125-d immature baboon. Ten 125-d gestation (term = 185 d) baboon dams were delivered after intra-amniotic inoculation with Uu. Serial blood and tracheal aspirate samples were analyzed for Uu colony-forming units, IL-6, IL-8, and cell counts. Physiologic parameters were serially recorded. Lung histology was examined after 14 d of ventilation and compared with unexposed controls. All Uu-exposed animals had >4 x 102 CFU in tracheal aspirate at 24 h. Four of nine Uu animals remained heavily colonized [(+) Uu] at necropsy (>6 x 103). Five animals had negative or low tracheal colony-forming units. All Uu animals had significant increases for white blood cells, IL-6, and IL-8 in amniotic and fetal lung fluid. Compared with controls, (+) Uu animals had significantly higher fraction of inspired oxygen, airway pressures, oxygenation index, and ventilation efficiency index between 48 and 240 h and had significantly elevated tracheal IL-6 and IL-8 concentrations between 72 and 240 h. Compared with controls (-) Uu animals had significantly better oxygenation index and ventilation efficiency index scores between 48 and 144 h. Lung histopathology in both Uu groups showed more severe bronchiolitis and interstitial pneumonitis compared with controls. Two patterns of disease were observed after Uu perinatal infection. Persistent colonization manifested a picture consistent with acute pneumonitis, worse lung function from 2 to 10 d, and prolonged elevated tracheal cytokines. Colonized animals that subsequently cleared Uu from the lung demonstrated early improved lung function compared with unexposed controls yet still manifested mixed bronchiolitis and interstitial pneumonitis at necropsy. Inherent immune system responses may determine outcome of perinatal Ureaplasma colonization.

Topics: Age Factors; Amniotic Fluid; Animals; Bronchopulmonary Dysplasia; Disease Models, Animal; Female; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Papio; Pregnancy; Respiratory Function Tests; Ureaplasma Infections; Ureaplasma urealyticum

The effect of new ventilation strategies on initial pulmonary inflammatory reaction was studied in a surfactant-depleted piglet model. Sixty minutes after induction of lung injury by bronchoalveolar lavage, piglets received either aerosolized FC77 (aerosol-PFC, 10 mL/kg/h, n = 5) or partial liquid ventilation (PLV) with FC77 at functional residual capacity volume (FRC-PLV, 30 mL/kg, n = 5), or at low volume (LV-PLV, 10 mL/kg per hour, n = 5), or intermittent mandatory ventilation (control, n = 5). After 2 h, perfluorocarbon application was stopped and intermittent mandatory ventilation continued for 6 h. After a total experimental period of 8 h, animals were killed and lung tissue obtained. mRNA expression of IL-1beta, IL-6, IL-8, and TGF-beta in porcine lung tissue was quantified using TaqMan real-time PCR and normalized to beta-actin (A) and hypoxanthine-guanine-phosphoribosyl-transferase (H). In the aerosol-PFC group, IL-1beta, IL-6, IL-8, and transforming growth factor (TGF)-beta mRNA expression in lung tissue was significantly lower than in the control group. Reduction was 95% for IL-1beta/H (p < 0.001), 73% for IL-6/H (p < 0.05), 87% for IL-8/H (p < 0.001), and 38% for TGF-beta/H (p < 0.01). A lower mRNA gene expression was also determined for IL-1beta and IL-8 when the aerosol-PFC group was compared with the LV-PLV group [91% for IL-1beta/H (p < 0.001), 75% for IL-8/H (p < 0.001)]. In the FRC-PLV group, mRNA expression of IL-1beta was significantly lower than in the control (p < 0.05) and LV-PLV (p < 0.01) group. In a surfactant-depleted piglet model, aerosol therapy with perfluorocarbon but not LV-PLV reduces the initial pulmonary inflammatory reaction at least as potently as PLV at FRC volume.

Topics: Aerosols; Animals; Bronchopulmonary Dysplasia; Disease Models, Animal; Fluorocarbons; Humans; Infant, Newborn; Interleukin-1; Interleukin-6; Interleukin-8; Lung; Pneumonia; Pulmonary Surfactants; RNA, Messenger; Swine; Transforming Growth Factor beta; Ventilation

An exaggerated inflammatory response occurs in infants who subsequently develop bronchopulmonary dysplasia (BPD). Ureaplasma urealyticum (Uu) is frequently isolated from cultures of tracheal secretions obtained from very low birth weight infants and is associated with an increased risk of BPD.. We examined the relationships between isolation of genital mycoplasmas, tracheal aspirate (TA) interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1) concentrations and the development of BPD. Serial TAs were obtained prospectively from 35 very low birth weight infants, and IL-8 and MCP-1 concentrations were determined by enzyme-linked immunoadsorbent assay. Tracheal cultures for bacteria and genital mycoplasmas were performed on aspirates obtained during the first 2 days of life.. Infants who developed BPD (n=18) were less mature (25.2+/-0.2 vs 27.8+/-0.5 weeks; P<0.001), of lower birth weight (746+/-28 vs 1052+/-41 g; P<0.001), and more likely to have a positive tracheal culture for Uu (39% vs 6%; P=0.026) than those who did not develop BPD (n=17). Tracheal concentrations of IL-8 and MCP-1 were significantly increased in infants who developed BPD (IL-8: P=0.0001; MCP-1: P<0.001, analysis of variance) and correlated with duration of mechanical ventilation and oxygen treatment. Uu-positive infants had an increased incidence of BPD (88% in infants with Uu vs 42% in infants without Uu; P=0.020) and had TA concentrations of IL-8 and MCP-1 that were significantly increased compared with those of Uu-negative infants.. Increased TA concentrations of IL-8 and MCP-1 during the first 2 weeks of life are associated with the development of BPD. Recovery of Uu from TAs is associated with a more robust inflammatory reaction and an increased risk of BPD.

Topics: Bronchopulmonary Dysplasia; Chemokine CCL2; Genitalia; Humans; Infant, Low Birth Weight; Infant, Newborn; Inflammation Mediators; Interleukin-8; Prospective Studies; Trachea; Ureaplasma Infections; Ureaplasma urealyticum

Intraamniotic endotoxin causes chorioamnionitis, which is followed by improved fetal lung function after 4 d in fetal sheep. We evaluated 0.1 mg, 1 mg, 4 mg, and 10 mg endotoxin for inflammation and lung maturation effects after 7 d. Four and 10 mg endotoxin caused similar lung maturation and inflammation in the lung and chorioamnion. The number of neutrophils in cord blood and the inflammatory cells in alveolar lavage and fetal lung tissue increased in a dose-dependent manner. Lower endotoxin doses induced indicators of chorioamnionitis, lung and systemic inflammation without inducing lung maturation. Therefore, some degree of inflammation can occur without subsequent lung maturation. The inflammatory changes caused by 4 mg endotoxin were assessed after 5 h, 24 h, 72 h, and 7 d to discern local versus systemic inflammation after intraamniotic endotoxin. At 5 h active inflammatory cells were in the airways producing hydrogen peroxide, and interleukin-6 and -8 were increased in the cord blood indicating both lung and systemic responses. Cells recruited into the amniotic fluid produced proinflammatory cytokine mRNA for 7 d with no cytokine mRNA in chorioamnion, lung, or spleen after 72 h. The cells in the amniotic fluid may be a source of prolonged fetal exposure to proinflammatory cytokines.

Topics: Amniotic Fluid; Animals; Animals, Newborn; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Chorioamnionitis; Cytokines; Data Interpretation, Statistical; Disease Models, Animal; Endotoxins; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Humans; Infant, Newborn; Inflammation; Interleukin-6; Interleukin-8; Male; Neutrophils; Pregnancy; Pulmonary Surfactants; Random Allocation; Respiratory Distress Syndrome, Newborn; RNA, Messenger; Sheep; Time Factors

The mechanism by which dexamethasone (DEX) inhibits neutrophil (PMN) recruitment to a site of inflammation, such as the newborn lung with bronchopulmonary dysplasia, is not completely understood. The aim of our study was to determine whether DEX inhibits neutrophil-induced neutrophil recruitment by inhibition of interleukin- (IL) 8 release from PMNs, and if there are developmental differences. PMNs isolated from cord blood (CB) and adults (A) were studied. We first measured the effect of DEX (10(-10) to 10(-4) M) on PMN migration to an exogenous IL-8 standard (10(-8) M) using PMNs of CB (n = 3) and A (n = 3), over 1 h in a chemotaxis chamber. Second, we determined the effect of DEX (0 and 10(-10) to 10(-6) M) on IL-8 release (immunoassay) from PMNs of CB (n = 7) or A (n = 7) after incubation with lipopolysaccharide (LPS, 1 ng/mL) for 6 and 18 h. Third, the chemoattractant activity of culture media from the second experiment was studied with and without IL-8 antibody. DEX at concentrations of 10(-10) to 10(-4) M had no direct effect on PMN migration in vitro to an exogenous IL-8 standard. After LPS exposure, IL-8 release was greatly increased for PMNs from CB compared with A. DEX (10(-10) to 10(-4) M) resulted in a dose-dependent inhibition of IL-8 release from PMNs exposed to LPS for 6 and 18 h incubation. Increased PMN migration activity was only found with media of PMNs of CB with no DEX. At 18 h, media-induced migration activity was decreased if DEX (10(-7) M), IL-8 antibody, or DEX (10(-7) M) with IL-8 antibody were present during the incubation with LPS: there was an 88, 86, and 101% reduction in migration activity, respectively. We conclude that DEX inhibits PMN-induced PMN migration, predominantly via inhibition of IL-8 release for PMNs of the newborn. We suggest that a 10-fold lowering of the standard DEX dose may effectively reduce lung inflammation in bronchopulmonary dysplasia.

Topics: Adult; Bronchopulmonary Dysplasia; Cell Movement; Dexamethasone; Fetal Blood; Humans; In Vitro Techniques; Infant, Newborn; Interleukin-8; Lipopolysaccharides; Neutrophils

To determine if an intrauterine sub-clinical inflammatory process is a risk factor for the development of bronchopulmonary dysplasia.. A cohort study was conducted in patients who met the following criteria: (1) Singleton gestation; (2) preterm labor or preterm premature rupture of the membranes; (3) amniocentesis for microbiologic studies of the amniotic fluid and (4) delivery between 24 and 28 weeks of gestation. Bronchopulmonary dysplasia was defined as the need for supplemental oxygen for 28 days or longer after birth, associated with compatible chest radiographic findings. Amniotic fluid interleukin-8, was measured using a specific immunoassay. Logistic regression analysis and bootstrap procedure were used for statistical purposes.. Forty-seven patients met the inclusion criteria for this study. Among these patients, the prevalence of bronchopulmonary dysplasia was 23.4% (11/47). Amniotic fluid culture was positive in 21 out of 47 (44.7%) patients. Median (range) amniotic fluid interleukin-8 concentration was higher in patients whose neonates subsequently developed bronchopulmonary dysplasia than in those who did not (17 [9.8-583.7] ng ml(-1) versus 9.6 [0.91-744] ng ml(-1), P=0.057). An amniotic fluid IL-8 level greater than 11.5 ng ml(-1) was far more common in mothers whose fetuses went on to develop bronchopulmonary dysplasia than in those who did not (10/11 [90.9%] versus 17/36 [47%]; P=0.01). This relationship remained significant even after correcting for the effect of gestational age and birthweight (Odds ratio: 11.9; P<0.05).. Sub-clinical intrauterine inflammation is a risk factor for the subsequent development of bronchopulmonary dysplasia. We propose that in utero aspiration of fluid with high concentration of pro-inflammatory mediators may contribute to the lung injury responsible for the development of bronchopulmonary dysplasia.

Topics: Amniotic Fluid; Birth Weight; Bronchopulmonary Dysplasia; Cohort Studies; Female; Fetal Membranes, Premature Rupture; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Interleukin-8; Logistic Models; Mycoplasma hominis; Obstetric Labor, Premature; Pregnancy; Risk Factors; Ureaplasma urealyticum

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

Our purpose was to test the hypothesis that neonates who develop bronchopulmonary dysplasia have higher amniotic fluid concentrations of proinflammatory cytokines than those who do not develop bronchopulmonary dysplasia.. The relationship between amniotic fluid concentrations of interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 and the occurrence of bronchopulmonary dysplasia in the neonate was examined in 69 patients who were delivered of preterm neonates (< or = 33 weeks) within 5 days of amniocentesis. Cytokines were measured by specific immunoassays.. Bronchopulmonary dysplasia was diagnosed in 19% (13/69) of newborns. Median amniotic fluid concentrations of interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 concentrations were significantly higher in mothers whose infants had bronchopulmonary dysplasia than in mothers whose infants did not have bronchopulmonary dysplasia (p < 0.05 for each). Neonates who had bronchopulmonary dysplasia were delivered at earlier gestational ages and had lower birth weights than those without bronchopulmonary dysplasia. The differences in median amniotic fluid interleukin-6, interleukin-1 beta, and interleukin-8 between these two groups remained significant after we adjusted for the effect of gestational age at birth (p < 0.05 for each).. (1) Antenatal exposure to proinflammatory cytokines is a risk factor for the development of bronchopulmonary dysplasia; (2) the injury responsible for bronchopulmonary dysplasia in a subset of neonates may begin before birth.

Topics: Adult; Amniotic Fluid; Bacteria; Bronchopulmonary Dysplasia; Cohort Studies; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Interleukin-1; Interleukin-6; Interleukin-8; Obstetric Labor, Premature; Pregnancy; Retrospective Studies; Risk Factors; Tumor Necrosis Factor-alpha

The influx of inflammatory mediators and cells into the tracheobronchial effluent of preterm infants with respiratory distress syndrome (RDS) appears to be important in signaling the development of bronchopulmonary dysplasia (BPD). The mechanism that initiates this early inflammatory response is not well understood. The purpose of this study was to test the hypothesis whether increased interleukin-8 (IL-8), a potent chemoattractant for human neutrophils, appears in the airways of preterm infants with RDS in whom BPD develops before the influx of neutrophils. In addition, airway secretions were analyzed for the cytokine interleukin-6 (IL-6) to test the hypothesis whether this pro-inflammatory cytokine is an early marker of inflammation in preterm infants with RDS who progress to BPD. Sixty-five infants less than 32 weeks gestation with RDS were enrolled on the first day of life and 56 infants completed the study, with 31 recovering from RDS (Non-BPD) and 25 infants progressing to BPD. Infants were excluded from enrollment in the presence of maternal chorioamnionitis, infection at birth, or infection within the first week of life. There were no significant differences in birthweight, gestational age, or prolonged rupture of membranes between the two groups. Serial tracheal aspirates (TA) were collected on days 1, 3, 5, and 7 while the infants remained intubated. Significant elevations of TA neutrophil counts were detected in the BPD group on days 5 and 7. Cell-free TA revealed marked elevations of IL-8 in the BPD group compared to the Non-BPD group [median (25th percentile, 75th percentile), ng/ml epithelial lining fluid (ELF)] on day 1 [BPD 485 (195, 840); Non-BPD 63.1 (28.3, 197), P < 0.05] and day 3 [BPD 740 (319, 1310); Non-BPD 111 (54.3, 337); P < 0.05], while on days 5 and 7, the differences were not statistically significant. Interleukin-6 (IL-6) was measured as a marker of acute inflammation and was not different in the two groups on day 1, but was significantly elevated on day 3 [median (25th percentile, 75th percentile), ng/ml ELF; BPD 297 (62.1, 702); Non-BPD 72 (32.8, 266), P < 0.05] and on day 5 [BPD 270 (136, 672); Non-BPD 86.4 (57.8, 138), P < 0.05]. These studies demonstrate that elevation of IL-8 and IL-6 levels precedes the marked neutrophil influx seen in the TA of preterm infants in whom BPD develop. The presence of IL-8 and IL-6 in TA from these infants suggests that these cytokines either initiate the acute inflammatory cascade in the

Topics: Biomarkers; Bronchopulmonary Dysplasia; Disease Progression; Female; Humans; Infant, Newborn; Infant, Premature; Interleukin-6; Interleukin-8; Male; Neutrophils; Predictive Value of Tests; Prospective Studies; Respiration, Artificial; Respiratory Distress Syndrome, Newborn; Sputum; Trachea

Chronic lung disease (CLD) of prematurity is associated with an initial increase in pulmonary neutrophils followed by pulmonary fibrosis. We determined whether the proinflammatory cytokines, IL-1 beta and IL-6, were increased in the bronchoalveolar lavage fluid obtained from nine infants (median gestation 25 wk, birthweight 820 g) who developed CLD, seven (28 wk, 1110 g) who recovered from the respiratory distress syndrome (RDS), and four (38 wk, 2690 g) control infants. IL-1 beta and IL-6 protein were both increased in the bronchoalveolar lavage fluid from the CLD groups when compared with the RDS and control groups. This difference for both the cytokines was most marked on d 10 of age, when results from infants with and without CLD were compared (IL-1 beta, 4.6 versus 1.1 ng/mL, p < 0.05; and IL-6, 9.5 versus 1.5 ng/mL, p < 0.05). Immunocytochemistry of lavage cells for IL-1 beta, IL-6, and IL-8 protein showed alveolar macrophages to contain all three cytokines, with lesser staining evident in neutrophils, and in epithelial cells occasionally obtained by lavage. The contribution of alveolar macrophages and luminal cells to the increase in IL-6 and IL-1 was determined by performing semiquantitative reverse transcription-polymerase chain reactions on RNA extracted from lavage cells. IL-6 mRNA expression was increased in lavage cells from the CLD infants when compared with the RDS group. However, the expression for IL-1 beta and IL-8 mRNA was similar in both groups. These results suggest that IL-1 beta, IL-6, and IL-8 may contribute to the pathogenesis of CLD, and that, in CLD, IL-6 may be produced by cells within the air spaces.

Topics: Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Case-Control Studies; Female; Gestational Age; Humans; Immunohistochemistry; Infant, Newborn; Infant, Premature, Diseases; Interleukin-1; Interleukin-6; Interleukin-8; Male; Polymerase Chain Reaction; Transcription, Genetic

Topics: Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Complement C5a; Humans; Infant, Low Birth Weight; Infant, Newborn; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-8; Leukotriene B4; Pancreatic Elastase

Bronchopulmonary dysplasia (BPD) of preterm neonates is associated with an increased recruitment of inflammatory cells into the airways. To evaluate further the role of inflammation in the pathogenesis of BPD, tracheobronchial aspirate fluid of neonates with birth weight < 1200 g (n = 59) was sequentially analyzed in a prospective study.. Tracheobronchial aspirate fluid was assessed for chemotactic activity, neutrophil cell count, concentrations of elastase-alpha 1-proteinase inhibitor and activity of free elastase, concentrations of chemoattractants (complement component C5-derived anaphylatoxin, leukotriene B4, interleukin-8), and albumin concentrations as well as alpha 1-proteinase inhibitor activity. The secretory component for immunoglobulin A was used as reference protein. Only specimens without evidence of microbiological colonization were studied.. In neonates with prolonged respiratory disease (BPD-risk neonates, n = 24, fraction of inspired oxygen > or = 0.3 and/or peak inspiratory pressure > or = 16 cm H2O at day 10 postnatal age, birth weight 892 +/- 36 g, gestational age 27.2 +/- 0.3 weeks) chemotactic activity, cell count, concentrations of the chemoattractants complement component C5-derived anaphylatoxin, leukotriene B4, interleukin-8, as well as levels of elastase-alpha 1-proteinase inhibitor were significantly higher at day 10 and/or day 15 of postnatal age compared with neonates without chronic pulmonary disease (total n = 35; day 10, n = 11; day 15, n = 8). There was no difference in free elastolytic activity. Concentrations of albumin as well as alpha 1-proteinase inhibitor activity were higher in BPD-risk patients on day 15, indicating an increased pulmonary leak.. We conclude that preterm neonates at risk for the development of BPD show an enhanced inflammatory reaction in the lungs and an associated increase in pulmonary microvascular permeability. We speculate that inflammation may play an important role in the pathogenesis of BPD.

Topics: Albumins; alpha 1-Antitrypsin; Bronchopulmonary Dysplasia; Capillary Permeability; Chemotaxis, Leukocyte; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-8; Leukocyte Count; Leukotriene B4; Lung; Neutrophils; Pancreatic Elastase; Prospective Studies; Respiratory Distress Syndrome, Newborn; Risk Factors

Multiple insults may induce bronchopulmonary dysplasia (BPD) in premature infants, including the recently reported association of BPD with neonatal Ureaplasma urealyticum colonization. One mechanism of damage could involve stimulation of proinflammatory cytokine release from pulmonary fibroblasts. We therefore compared the effects of U. urealyticum, oxygen, and lipopolysaccharide (LPS) on the release of interleukin (IL)-1 beta, IL-6, and IL-8 from neonatal fibroblasts. Fibroblasts were grown in multiwell plates and divided into the following experimental conditions: fibroblasts alone, fibroblasts plus U. urealyticum (10,000 cfu/mL), and fibroblasts plus LPS (2 micrograms/mL). Plates were then exposed to room air or hyperoxia for 48 h, and supernatants were assayed for IL. U. urealyticum-infected fibroblasts produced a significant increase in IL-6 (P < .05) and a dramatic increase in IL-8 (P < .05) that was independent of hyperoxic exposure and significantly increased over that produced by LPS or hyperoxia alone. U. urealyticum is a potent inducer of fibroblast cytokine release in vitro and may contribute to the development of BPD.

Topics: Bronchopulmonary Dysplasia; Cell Line; Fibroblasts; Humans; Infant, Newborn; Interleukin-1; Interleukin-6; Interleukin-8; Interleukins; Lung; Oxygen; Ureaplasma Infections; Ureaplasma urealyticum