Nasal lavage leukotrienes in infants with RSV bronchiolitis

Respiratory syncytial virus (RSV) bronchiolitis is a very common infection in infants and, after the acute phase, a number of patients develop a reactive airway disease that lasts for years. Although the pathogenesis of the lung damage after RSV bronchiolitis is still largely unknown, previous studies suggest that leukotrienes may play an active part in it. The aim of this study was to measure leukotriene levels in the nasal lavage fluid (NLF) collected in infants during RSV bronchiolitis and 1 month later. Cysteinyl leukotrienes (Cys-LTs) and leukotriene B(4) (LTB(4)) were measured in the NLF of 22 infants with their first episode of RSV bronchiolitis and 16 healthy infants. A second NLF sample was collected to measure leukotriene levels 1 month after the acute disease. NLF Cys-LT levels were significantly higher in infants with RSV bronchiolitis than in healthy controls [950 pg/ml (285.5-2155.9) vs. 110.5 pg/ml (66.5-451.3), p = 0.01], and they remained so a month after the acute infection (p = 0.02). A subanalysis showed no difference in Cys-LTs concentrations, either between bronchiolitis infants with and without a family history of atopy, or between those with and without passive exposure to cigarette smoke. No significant difference was found between the LTB(4) levels measured in the bronchiolitis cases and the control children. Cys-LTs are significantly increased in the NLF of infants with acute RSV bronchiolitis, and remain so at 1-month follow-up, suggesting a possible role of these eicosanoids in the pathogenesis of the disease.     

Eosinophil cationic protein in tracheal aspirates of preterm infants with bronchopulmonary dysplasia

Eosinophil cationic protein was elevated during the first week of life in tracheal aspirates from 11 preterm infants in whom bronchopulmonary dysplasia subsequently developed compared with 8 preterm and 8 term infants without bronchopulmonary dysplasia. Eosinophil cationic protein levels increased progressively with continued intubation in the infants with bronchopulmonary dysplasia but remained low in a comparison group of term infants. We suggest that eosinophils participate in the inflammatory process in bronchopulmonary dysplasia and may contribute to lung injury. (J Pediatr 1997;130:944-7)     

Effect of dexamethasone therapy on fibronectin and albumin levels in lung secretions of infants with bronchopulmonary dysplasia.

The influence of dexamethasone on levels of total fibronectin (tFn), cellular fibronectin (cFn), plasma fibronectin (pFn), and albumin in lung secretions was determined in tracheal aspirate samples collected from 45 infants with bronchopulmonary dysplasia during a 6-week course of dexamethasone therapy. Secretory component for IgA (SC) was used as a reference protein. Thirty-seven infants (82%) survived and had their endotracheal tubes successfully removed. Corticosteroid therapy was associated with a significant decrease in the cFn/SC ratio. There was also a significant decrease in albumin/SC and pFn/SC ratios, suggesting decreased capillary permeability with corticosteroid therapy. Four of the remaining infants did not improve while receiving corticosteroids and died of respiratory failure at 3 to 8 weeks of age. In these "no response" infants, tFn/SC, cFn/SC, pFn/SC, and albumin/SC ratios when corticosteroid therapy was initiated were threefold to fourfold greater (p < 0.01) than ratios in survivors. Another group of four infants initially responded to corticosteroids but subsequently died with severe pulmonary cystic degeneration at 4 to 6 months of age; in these infants, tracheal aspirate tFn/SC, cFn/SC, and albumin/SC ratios were significantly lower than in survivors and remained unchanged during corticosteroid therapy. The decrease in the concentrations of plasma fibronectin and albumin in tracheal aspirate samples from the survivors suggests that the rapid clinical improvement seen in infants with bronchopulmonary dysplasia after the initiation of dexamethasone therapy is due in part to improvement in the integrity of the alveolar-capillary barrier. In addition, the decrease in the aspirate levels of cFn suggests the potential for corticosteroids to limit pulmonary fibrosis in the surviving infants. The depressed levels of fibronectin observed in the infants with severe cystic lung disease may represent an impaired healing response to lung injury.     

Tracheal lavage and plasma fibronectin: relationship to respiratory distress syndrome and development of bronchopulmonary dysplasia

Plasma for fibronectin determinations was obtained from 39 neonates with uncomplicated respiratory distress syndrome (RDS) and from 15 infants with RDS who developed bronchopulmonary dysplasia (BPD). Tracheal lavage fibronectin and albumin concentrations were measured in 15 infants with RDS and 15 with BPD. Control plasma fibronectin values were obtained from 20 healthy preterm infants on days 1, 2, 3, 14, and 30 of life. Control tracheal lavage fibronectin and albumin concentrations were measured in 17 neonates of various gestational ages who required tracheal intubation for nonpulmonary indications. Mean plasma fibronectin concentrations from patients with RDS was 121 +/- 11 micrograms/ml on days 1, 2, and 3, versus control level of 163 +/- 12 micrograms/ml (P less than 0.01). Mean tracheal lavage fibronectin/albumin ratio was 3.8 +/- 0.6 ng per microgram of albumin on days 1 to 5 for infants with RDS, versus control level of 5.6 +/- 3.6 (P = NS). Tracheal lavage fibronectin/albumin ratio from patients with BPD was elevated at 16.3 +/- 5.0 ng fibronectin per microgram of albumin on days 14 to 21, and 23.6 +/- 7.4 on day 30 (P less than 0.05 versus control and and versus RDS days 1 to 10). Low plasma fibronectin concentrations early in RDS may contribute to the development of pulmonary capillary leak. High tracheal lavage fibronectin levels may foster the development of pulmonary fibrosis in patients with BPD.     

Comparison of tracheal aspirate and bronchoalveolar lavage specimens from premature infants

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.     

Elevated type IV collagen in bronchoalveolar lavage fluid from infants with bronchopulmonary dysplasia

We measured the levels of type IV collagen and lipid peroxides in bronchoalveolar lavage fluid (BALF) from infants with respiratory distress syndrome (RDS) to determine the relationship to the development of bronchopulmonary dysplasia (BPD). We analyzed their levels between two groups, RDS infants who developed BPD (n = 8, BPD group) and those who did not (n = 11, RDS group). The levels of the type IV collagen in the BPD group were significantly higher than those in the RDS group at 3 and 7 days of age (p = 0.0024). In the BPD group, persistently increased levels of the type IV collagen were observed during the period up to 14 days of age. There was a positive relationship between the type IV collagen levels and polymorphonuclear leukocyte counts, and thiobarbituric acid-reactive substance levels in BALF. These results suggest that the increased type IV collagen levels in BALF of BPD infants may reflect pulmonary basement membrane damage and the involvement of oxygen metabolites in its process.     

Microscopic observations on tracheal aspirates from ventilated neonates

A total of 450 undiluted and unprocessed tracheal aspirates from 120 intubated infants were examined microscopically for evidence of bronchopulmonary dysplasia and other changes. In 19 infants desquamated sheets of dysplastic epithelium in the fresh aspirate provided an early indication of developing bronchopulmonary dysplasia. Examination of unstained tracheal aspirates can provide, within minutes, information not only about the onset and development of bronchopulmonary dysplasia, but also provide evidence for milk or formula aspiration and for gastro-oesophageal reflux.     

Haplotypes of tumor necrosis factor gene and tracheal aspirate fluid levels of tumor necrosis factor-alpha in preterm infants

Individual variability in the production of tumor necrosis factor-alpha (TNF-alpha) has been attributed to genetic factors. We examined whether alleles of TNF gene (lymphotoxin-alpha+250, TNF-alpha-308, and TNF-alpha-238) affect tracheal aspirate fluid (TAF) levels of TNF-alpha among preterm infants at risk of bronchopulmonary dysplasia. TAF samples were collected within 48 h of birth and 7, 14, 21, and 28 d later. Haplotypes [designated using the nucleotide bases in the chromosome order (lymphotoxin-alpha+250, TNF-alpha-308, TNF-alpha-238)] of TNF were correlated with levels of TNF-alpha. Diplotypes of TNF (genotypes of haplotypes) classified as high, intermediate, or low based on their relation to TAF TNF-alpha levels were also correlated with TNF-alpha levels. The most frequent (and reference haplotype) was AGG. The GGG haplotype was associated with the lowest TAF TNF-alpha levels on day 7 among African American infants (p < 0.008). Sequential changes in levels of TNF-alpha correlated with infants' diplotype status [high (HH), intermediate (HL), low (LL)]. Fetal chorioamnionitis but not bronchopulmonary dysplasia was associated with infants' diplotypes (p < 0.005). Haplotypes of the TNF gene influence TAF levels of TNF-alpha. Diplotypes of TNF are associated with fetal chorioamnionitis.     

Invasive mechanical ventilation and biomarkers as predictors of bronchopulmonary dysplasia in preterm infants

ObjectivesTo evaluate the impact of invasive mechanical ventilation associated with two serum inflammatory cytokines and clinical indicators, on the second day of life, as predictors of bronchopulmonary dysplasia in very low birth weight preterm infants. It was hypothesized that the use of invasive mechanical ventilation in the first hours of life is associated with biomarkers that may predict the chances of preterm infants to develop bronchopulmonary dysplasia.MethodsProspective cohort of 40 preterm infants with gestational age <34 weeks and birth weight <1500 g. The following were analyzed: clinical variables; types of ventilator support used (there is a higher occurrence of bronchopulmonary dysplasia when oxygen supplementation is performed by long periods of invasive mechanical ventilation); hospitalization time; quantification of two cytokines (granulocyte and macrophage colony stimulating factor [GM-CSF] and eotaxin) in blood between 36 and 48 h of life. The preterm infants were divided in two groups: with and without bronchopulmonary dysplasia.ResultsThe GM-CSF levels presented a significantly higher value in the bronchopulmonary dysplasia group (p = 0.002), while eotaxin presented higher levels in the group without bronchopulmonary dysplasia (p = 0.02). The use of continuous invasive mechanical ventilation was associated with increased ratios between GM-CSF and eotaxin (100% sensitivity and 80% specificity; receiver operating characteristic area = 0.9013, CI = 0.7791–1.024, p < 0.0001).ConclusionsThe duration of invasive mechanical ventilation performed in the first 48 h of life in the very low birth weight infants is a significant clinical predictor of bronchopulmonary dysplasia. The use of continuous invasive mechanical ventilation was associated with increased ratios between GM-CSF and eotaxin, suggesting increased lung injury and consequent progression of the disease.     

Bronchopulmonary dysplasia: possible relationship to pulmonary edema

The pathogenesis of bronchopulmonary dysplasia is controversial. Oxygen toxicity, mechanical trauma to the lung secondary to respirator therapy, and congestive heart failure with a left to right shunt through a patent ductus arteriosus have all been implicated. Our data suggest that in addition to these three conditions, all of which are edemagenic, infants with bronchopulmonary dysplasia have a significantly greater mean fluid intake in the first five days of life when compared with infants with respiratory distress syndrome or patent ductus arteriosus alone. We suggest that the addition of a fluid load may potentiate the effects of other factors and increase the risk of bronchopulmonary dysplasia in infants with respiratory distress syndrome who require respiratory support.     

Bronchopulmonary dysplasia

OBJECTIVE: To review the literature on bronchopulmonary dysplasia. METHODS: The most important articles on bronchopulmonary dysplasia were selected through MEDLINE. RESULTS: The present review analyzes the different concepts, pathogenesis, clinical presentation, treatment and prophylaxis of bronchopulmonary dysplasia. CONCLUSIONS: bronchopulmonary dysplasia is a frequent condition of very low birth weight infants with hyaline membrane disease who require mechanical ventilation. The pathogenic factors are prematurity, oxygen therapy, mechanical ventilation, pulmonary edema, and infection. Treatment is based on good oxygenation, fluid restriction, nutritional support, diuretics, betamimetic drugs, xanthines, and steroids. Prophylaxis includes avoiding prematurity and using pre-natal steroids, superoxide dismutase, and post-natal steroids.     

Rate of bronchopulmonary dysplasia as a function of neonatal intensive care practices.

Some differences among neonatal intensive care units (NICUs) in incidence of bronchopulmonary dysplasia may reflect variations in medical care practices. After adjusting for differences in the inherent risk of bronchopulmonary dysplasia among 223 infants of less than 1751 gm birth weight who were admitted to three Harvard-affiliated NICUs, we used multivariate analysis to explore the extent to which medical care practices during the first days of life varied with the rate of bronchopulmonary dysplasia. In our analyses, variables were grouped by three major hypotheses: oxygen toxicity, barotrauma, and fluid overload. The NICU designated 1 (the one with the highest rate of bronchopulmonary dysplasia) used much higher than expected colloidal volumes during the first 4 days of life; in contrast, in the NICU designated 3 (the one with the lowest rate of bronchopulmonary dysplasia), infants consistently received lower than expected amounts of colloidal solution. Signs of patent ductus arteriosus were also much more frequent than expected during this time at NICU 1; rates were much lower than predicted at NICU 2 and were near predicted values at NICU 3. Maximum inspired oxygen fraction during the first 4 days varied significantly in a direction inconsistent with the oxygen toxicity hypothesis. Maximum arterial oxygen tension was significantly less than expected at the hospital with the lowest rate of bronchopulmonary dysplasia (NICU 3). None of six medical care practices indicating potential for barotrauma varied with NICU expect for positive end-expiratory pressure, which varied in a direction suggesting a protective effect against bronchopulmonary dysplasia. These findings agree best with the hypothesis that differences in hydration during the first days of life account for some of the difference among NICUs in bronchopulmonary dysplasia occurrence.     

Growth failure in infants with bronchopulmonary dysplasia: nutrition and elevated resting metabolic expenditure

The mechanisms underlying growth failure in infants with bronchopulmonary dysplasia are poorly understood. Thirteen infants with bronchopulmonary dysplasia at 6 months of corrected age and 12 full-term healthy control infants matched for age or size were studied. Resting oxygen consumption was measured during natural sleep, and an estimation of the resting metabolic expenditure by indirect calorimetry was performed. Growth parameters were measured, and a nutritional profile including dietary intake, stool analysis, and serum albumin, cholesterol, glucose, and prealbumin was obtained. Seven of the 13 infants with bronchopulmonary dysplasia had growth failure (defined as length and weight less than the tenth percentile of the Babson growth curves). These infants had lower birth weight, lower gestational age, and a greater number of days spent in supplemental oxygen or on mechanical ventilation. There was no statistical difference between the bronchopulmonary dysplasia-growth failure and bronchopulmonary dysplasia-normal growth infants for dietary intake or stool or serum analyses. However, serum prealbumin showed a significant linear correlation with body weight in infants with bronchopulmonary dysplasia. Resting metabolic expenditure was elevated in infants with bronchopulmonary dysplasia with growth failure and was inversely correlated with body weight in all infants with bronchopulmonary dysplasia. Thus, infants with bronchopulmonary dysplasia and growth failure have increased metabolic demands and decreased prealbumin values suggesting a relative state of protein-calorie malnutrition.     

Lung protective strategies for premature infants]

Despite many advances in perinatal medicine, bronchopulmonary dysplasia still frequently occurs in very premature infants. The very fragile lungs of these infants therefore have to be protected from birth. The protective strategies consist in applying positive expiratory pressure immediately, and using exogenous surfactant in a prophylactic or early use approach. The recent, variable flow, continuous positive airway pressure (CPAP) systems are very efficient and may allow to avoid tracheal intubation, or to facilitate weaning. When mechanical ventilation has to be used, high peak pressure and/or high tidal volume have to be avoided in order to prevent volutrauma. Accepting not to normalize PCO(2) contributes to it. High frequency oscillatory ventilation, which actually does not prevent bronchopulmonary dysplasia, is an extremely efficient ventilatory support technique for severe respiratory failure. Postnatal gluco-corticoid use reduces the rate of bronchopulmonary dysplasia at 36 weeks, but also results in an increased incidence of long-term neurological handicaps. In our experience, using these treatments can be avoided. Maternal transfer to a level three perinatal center, associated with the adequate use of theses lung protective strategies following very premature birth enable the less unfavorable results to be obtained.     

Hypoxic airway constriction in infants of very low birth weight recovering from moderate to severe bronchopulmonary dysplasia

We hypothesized that infants recovering from severe bronchopulmonary dysplasia have airway constriction that is, at least in part, related to borderline hypoxia. If this hypothesis were correct, pulmonary resistance should decrease with the administration of oxygen. To test this hypothesis, we studied 10 infants recovering from severe bronchopulmonary dysplasia (study weight 2490 +/- 275 gm; birth weight 1010 +/- 89 gm; postnatal age 73 +/- 7 days; postconceptional age 38.5 +/- 1.6 weeks) and 10 matched control infants (study weight 2430 +/- 179 gm; birth weight 2320 +/- 195 gm; postnatal age 25 +/- 4 days; postconceptional age 37.5 +/- 0.8 weeks). Resistance and compliance were measured by means of a mask with a flowmeter and an esophageal balloon (with the PEDS computer program). Measurements in both groups were made in quiet sleep, without sedation, during the inhalation of room air and during the fifth minute of oxygen inhalation. We found that (1) total pulmonary resistance, significantly higher in infants with bronchopulmonary dysplasia than in control infants, decreased from 206.1 +/- 47 cm H2O.L-1.sec-1 during inhalation of room air to 106.5 +/- 20.9 during inhalation of 100% oxygen (p less than 0.05) and (2) pulmonary dynamic compliance, lower in infants with bronchopulmonary dysplasia than in control infants, increased significantly with the administration of 100% oxygen. The results suggest that infants with bronchopulmonary dysplasia have airway constriction and that this is alleviated by inhalation of oxygen.     

KL-6在肺部疾病中的研究进展

KL-6为肿瘤分化抗原,是一种跨膜高分子量的黏蛋白.近年来研究发现某些疾病,如间质性肺疾病、急性肺损伤、肿瘤及早产儿支气管肺发育不良等,患者血清及支气管肺泡灌洗液中KL-6水平不同程度的升高,因此建议把KL-6作为间质性肺疾病和肿瘤的临床早期诊断、疗效评价和转归评估的参考指标,但有关KL-6在不同疾病进程中的分子生物学机制尚有待于进一步研究.     

Bronchopulmonary dysplasia and oxidative stress: are we closer to an understanding of the pathogenesis of BPD?

In recent years a body of data has accumulated, linking the development of bronchopulmonary dysplasia (BPD) to increased oxidative stress in the first few days after birth, since high concentrations of metabolites reflecting increased peroxidation products such as pentane, ethane, protein carbonyl, o -tyrosine, allantoin and F₂-isoprostanes, as well as low levels of glutathione and sulfhydryl/total protein ratio, also reflecting increased oxidative load, have been found in the premature infants at risk of or developing BPD. Oxidative stress seems to increase lung antioxidants in some experimental models of BPD and hyperoxia affects foetal lung growth. There are similarities between inflammation and hypoxia/reoxygenation, since both activate a number of inflammatory mediators such as cytokines and adhesion molecules, some of which are found in high concentrations in tracheal aspirate fluid of infants developing BPD. Surfactant production and function are also altered by both hyperoxia and reactive oxygen species per se , making the lungs more vulnerable to injury. This new knowledge may result in new and more efficient therapeutic approaches, hopefully leading to the eradication of BPD in the near future.     

Early protein oxidation in the neonatal lung is related to development of chronic lung disease

Free radical-mediated oxidation of proteins may impair their function and cause cellular damage. We studied pulmonary protein oxidation and its association with the development of chronic lung disease in 61 newborn infants (mean gestational age 31.1 ± 4.0, range 24-41 weeks) requiring intensive care with oxygen therapy. Protein oxidation was quantified as protein carbonylation in tracheal aspirates recovered daily during the first week of life. Mean carbonyl concentration was 3.5 ± 1.6 μmol/mg protein. Negative correlations existed between protein carbonylation during days 2-4 and gestational age (day 2: r = -0.37, p = 0.01; day 3: r = -0.48, p = 0.001; and day 4: r = -0.33, p = 0.03). Patients who developed bronchopulmonary dysplasia showed significantly higher protein carbonylation on days 1-6 (all p < 0.05). In multiple regression analysis explaining bronchopulmonary dysplasia, using gestational age, inspired oxygen on days 1-3 and protein carbonylation on day 3 as independent variables, only protein carbonylation remained significant. We conclude that immaturity is the most important factor explaining free radical-mediated pulmonary protein oxidation in newborn infants and that oxidation of proteins is related to the development of chronic lung disease.     

Growth and development of preterm infants with respiratory distress syndrome and bronchopulmonary dysplasia

This study examines the growth and development of 37 preterm infants, 20 with respiratory distress syndrome and 17 with bronchopulmonary dysplasia. The groups were balanced by sex, parity, family configuration, and socioeconomic status and were studied at either 12 or 18 months after hospital discharge. Findings indicate that infants with bronchopulmonary dysplasia are at greater risk for growth retardation in their second year than infants with respiratory distress syndrome. Furthermore, results from cognitive, sensorimotor, and language measures (the Bayley, Uzgiris-Hunt, and Receptive-Expressive Emergent Language scales) demonstrate that infants with bronchopulmonary dysplasia perform significantly less well than infants with respiratory distress syndrome. The group performance of the infants with respiratory distress syndrome suggests that their developmental scores are comparable to those of average, healthy full-term infants of the same age. In contrast, the group of infants with bronchopulmonary dysplasia performed in the low-average to delayed range. Moreover, regression analyses show that type of respiratory illness explains more of the variance in cognitive outcomes than such neonatal factors as birth weight or gestational age. Thus, this study demonstrates that infants with bronchopulmonary dysplasia are at high risk for developmental problems in their second year, and that the contribution of bronchopulmonary dysplasia to explanations of differential cognitive outcomes cannot be reduced to between-group differences in perinatal status.     

Azithromycin suppresses activation of nuclear factor-kappa B and synthesis of pro-inflammatory cytokines in tracheal aspirate cells from premature infants

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.