Cystic fibrosis in three children with bronchopulmonary dysplasia

Cystic fibrosis (CF) and bronchopulmonary dysplasia (BPD) are two common causes of chronic lung disease in children. Patients with BPD or CF often have recurrent respiratory symptoms, failure to thrive, and/or metabolic alkalosis during infancy and childhood. Thus, recognizing the diagnosis of CF in an infant with BPD can be difficult. We present three infants with both BPD and CF. The infants shared a history of respiratory distress and prolonged oxygen requirements. All three also had difficulty gaining weight, even after pancreatic enzyme supplementation was instituted. Metabolic alkalosis was observed in two infants. Previous studies in children with CF suggest that early diagnosis may impact both lung health and nutritional status. A high index of suspicion is necessary for clinicians to identify these children early and intervene with appropriate therapy.     

Recent Advances in Bronchopulmonary Dysplasia: Pathophysiology,Prevention, and Treatment

Bronchopulmonary dysplasia (BPD) is potentially one of the most devastating conditions in premature infants with longstanding consequences involving multiple organ systems including adverse effects on pulmonary function and neurodevelopmental outcome. Here we review recent studies in the field to summarize the progress made in understanding in the pathophysiology, prognosis, prevention, and treatment of BPD in the last decade. The work reviewed includes the progress in understanding its pathobiology, genomic studies, ventilatory strategies, outcomes, and therapeutic interventions. We expect that this review will help guide clinicians to treat premature infants at risk for BPD better and lead researchers to initiate further studies in the field.     

Dysplasia: a review

Bronchopulmonary dysplasia (BPD) is a common perinatal complication of very low birth weight preterm infants with a significant risk of long-term disability and morbidity. While clinical conditions such as prematurity and mechanical ventilation are its major risk factors, studies suggest that there is an individual susceptibility to BPD. This comprehensive review summarizes data collected about the implication of genetic polymorphisms in BPD and in its risk factors. Some studies have directly related the risk of BPD to genotype. Indeed, carrier states of genetic variants of cytokines (IFNgamma T+874A), adhesion molecules (L-selectin-Pro213Ser), elements of renin-angiotensin system (ACE-I/D), antioxidant enzymes (GST-P1 Val105Ile), and surfactant proteins (SPA1, SPB intron 4) has been identified as risk factors to BPD. Other studies investigated the role of genotype in BPD risk factors. Premature birth has been linked to carrier states of genetic variants with an impact on immune status (such as IL-6 G(-174)C, MBL2 54G/A, VEGF G+405C, HSP72 A+1267G genes) and matrix metalloproteases. Fetal inflammatory response syndrome, a major determinant of BPD is also affected by genotype (including LTalpha A+250G). Disturbed intrauterine lung development and vascularization may also contribute to BPD; these processes may be impaired in the presence of some rare genetic mutations. Furthermore, there is also a genetic component in the susceptibility to other perinatal adaptational disturbances such as respiratory distress syndrome that are associated with an increased need for mechanical ventilation, and, hence, with lung damage. The genetic variants presented in this article may help to identify infants at risk for BPD.     

A comprehensive approach to the prevention of bronchopulmonary dysplasia

The current bronchopulmonary dysplasia (BPD) is seen in infants born extremely premature, with less severe respiratory distress syndrome (RDS) and who received prenatal steroids-"new BPD". The pathophysiology of BPD is based on an impairment of lung maturation with prenatal and postnatal multi-hit insults and genetic susceptibility. This multifactorial pathophysiology of BPD suggests that no single "magic bullet" will prevent it. Thus, to avoid BPD we need to implement a complex and comprehensive strategy. This strategy is based on ventilatory and non-ventilatory measures. The ventilatory route allows an individualized endotracheal intubation approach. Early lung recruitment with nasal respiratory support (nasal continuous positive airway pressure [NCPAP] or nasal intermittent positive pressure ventilation [NIPPV] / synchronized NIPPV [SNIPPV]) and the INSURE (intubation, surfactant and early extubation) approach are discussed. Initial treatment with NCPAP did not reduce the rate of BPD compared to endotracheal ventilation and surfactant administration. While NIPPV/SNIPPV may have short-term advantages over NCPAP, the effect on BPD needs to be further studied. During hospitalization the respiratory goals should aim for adequate oxygenation, permissive hypercapnia, and gentle ventilation. However, these goals were found to have short-term benefits but did not reduce significantly the rate of BPD. Selective use of a short course of low dose corticosteroids can be considered after the first or second week of life in infants who are unable to be weaned from the ventilator and are at high risk for BPD. Non-ventilatory measures include early nutritional support with fluid restriction, caffeine and consideration of vitamin A. Hemodynamic significant patent ductus arteriosus (PDA) may be associated with BPD, but medical or surgical treatment of PDA were not shown to decrease BPD. Each component and the strategy as a whole needs to be further studied in large randomized prospective studies or by meta-analyses, especially in the target population of extremely premature infants who are the most prone to BPD.     

Prediction of neurodevelopmental outcome in infants with and without bronchopulmonary dysplasia

In a group of 236 very low birth weight (VLBW) surviving infants, 60 had developed bronchopulmonary dysplasia (BPD) in the nursery. When compared with the 176 infants without BPD, infants with BPD were smaller, more immature, with lower one- and five-minute Apgar scores. Infants with BPD had a greater incidence of cardio-pulmonary and central nervous system (CNS) complications in the nursery. On follow-up, 25 (42%) of these infants were abnormal developmentally compared to 7% of infants without BPD (p less than .001). When comparisons were made within the group of infants with BPD, very few differences were found in maternal or infant risk factors between the normal and abnormal infants. The infants with BPD who had poor outcome more often had seizures and severe intraventricular hemorrhage (IVH). The infants with BPD who had good outcome were more often small for gestational age (SGA) and resuscitated with intubation at birth. They had apnea in the nursery more frequently than did abnormal infants with BPD. We conclude that VLBW infants with BPD are at greater risk for poor neurodevelopmental outcome than those without BPD. The risk for the infant with BPD relates to CNS complications rather than to chronic lung disease.     

Urinary leukotriene E(4) excretion during the first month of life and subsequent bronchopulmonary dysplasia in premature infants

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

Severity of bronchopulmonary dysplasia and increased risk of feeding desaturation and growth delay in very low birth weight preterm infants

Oral feeding has been reported to compromise breathing among preterm infants with bronchopulmonary dysplasia (BPD) during hospitalization or shortly after discharge. However, limited information was available concerning whether preterm infants with BPD remain vulnerable to feeding and growth insufficiency after a longer term of follow‐up. The purpose of this study was therefore to examine the effect of severity of BPD on pulse oxygen saturation (SpO₂) during feeding and growth in very low birth weight (VLBW) preterm infants during infancy. Seventy‐two preterm infants with VLBW and 15 term infants were prospectively examined their growth and SpO₂ during feeding at 2, 4, and 6 months of corrected age. The severity of BPD was graded in VLBW infants according to the American National Institutes of Health consensus definition. In comparison to VLBW infants with mild BPD and term infants, VLBW infants with severe BPD showed significantly lower mean levels of SpO₂ during feeding at 2–6 months corrected age (P < 0.05). Those with severe BPD further exhibited higher rates of growth delay (weight < 10th percentile) throughout the study period. Among VLBW infants, severe BPD had an adverse relation with subsequent weight measures after adjustment for medical and demographic confounding variables (β = ?904 g, P = 0.03). The consensus BPD definition is useful to identify those preterm infants who are at greater risk of feeding desaturation and growth delay during infancy and close monitoring of SpO₂ during feeding should be advised. Pediatr Pulmonol. 2010; 45:165–173. © 2010 Wiley‐Liss, Inc.     

Respiratorische Langzeitfolgen nach Frühgeburt

The paper reviews the current literature on the long-term impact of bronchopulmonary dysplasia (BPD) on respiratory health in adolescence and early adulthood. A significant proportion of preterm infants suffering from BPD demonstrate persistent respiratory abnormalities into adulthood. These include an obstructive pattern of lung function with increased trapped air, obstructive symptoms during infections, decreased exercise tolerance and computer tomographic findings with emphysematous changes and increased subpleural and peribronchial thickening. Evidence is accumulating that BPD in infancy confers a risk for later chronic obstructive pulmonary disease (COPD) like disease.     

Blunted peripheral chemoreceptor response to hyperoxia in a group of infants with bronchopulmonary dysplasia

Infants with BPD often suffer from chronic hypoxia and require supplemental oxygen (O₂). This might affect the sensitivity of peripheral chemoreceptors. Therefore, we assessed peripheral chemoreceptor function in 25 infants with bronchopulmonary dysplasia (BPD) of varying severity, using the hyperoxic test. These infants were compared with 35 preterm infants who did not develop BPD. All infants were tested during the 40th week of postconceptional age and their mean postnatal age was 81.5 ± 16.3 days. Sixty percent (15/25) of the BPD infants lacked a hyperoxic response, while the proportion of nonresponders to O₂, among the other groups was 20% (7/35). The intensity of this response was negatively correlated to time spent on a ventilator and positively to time without supplemental oxygen. The intensity of chemoreceptor function was closely related to the severity of BPD; none of the infants with the most severe form of BPD (grade 3) showed a ventilatory response to hyperoxia. Furthermore, infants with BPD needed significantly longer time to increase their saturation than did non-BPD infants (4.7 and 9.3 sec, respectively). We conclude that many infants with BPD, particularly those with the most severe form of the disease, have abnormally functioning peripheral chemoreceptors. Pediatr Pulmonol. 1995; 20:101–106 . © 1995 Wiley-Liss, Inc.     

Urine bombesin-like peptide elevation precedes clinical evidence of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of very low birth weight infants, associated with oxygen therapy, barotrauma, and/or infections. Improved medical care has led to a paradoxically increased incidence of BPD due to greater infant survival. Early prediction of BPD has proven challenging. Increased pulmonary neuroendocrine cells containing bombesin-like peptide immunoreactivity occur in infants with BPD. We hypothesized that elevated urine bombesin-like peptide levels precede BPD. One hundred thirty-two infants, 28-weeks gestation or less, were studied. Urine bombesin-like peptide levels, determined by radioimmunoassay, were normalized for creatinine. BPD was defined as oxygen dependence at 36 weeks postmenstrual age. A first urine bombesin-like peptide level greater than 20,000 pg/mg creatinine (12,500 fmol/mg) between postnatal days 1-4 occurred among 54% of the infants who later developed BPD (p < or = 0.001), versus 10% among non-BPD infants (specificity 90%). Multivariable logistic regression analyses revealed that elevated urine bombesin-like peptide levels are associated with BPD (odds ratio 9.9, 95% confidence interval: 3.4, 29) (p < or = 0.001) after adjusting for all confounding factors. Thus, elevated bombesin-like peptide levels in these infants at 1-4 days after birth are associated with a 10-fold increased risk of developing BPD. Utilizing urine bombesin-like peptide for screening might permit early therapeutic interventions to reduce disease progression and could provide a target for new preventive therapies.     

Clara cell secretory protein oxidation and expression in premature infants who develop bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects prematurely born infants and appears to evolve in part from early inflammatory responses in the lung. The inflammatory responses have been associated with protein and lipid oxidation in tracheal aspirate fluids. The present study was designed to test the hypothesis that in the first week of life specific oxidations and/ or altered expressions of proteins would be observed in tracheal aspirate fluids in infants who would subsequently develop BPD. We obtained tracheal aspirate fluids on Days of life 1, 3, and 6 from infants born at < or = 29 wk gestation, incubated the fluids with 2,4-dinitrophenylhyrazine (DNPH), separated the proteins electrophoretically, and assessed DNPH reactivity by immunonblots. DNPH reactivity of a protein that was identified as Clara cell secretory protein (CCSP) was observed more consistently in tracheal aspirate fluids from infants who later developed BPD than from infants who did not develop BPD. Tracheal aspirate fluid levels of immunoreactive CCSP were also lower on Day of life 1 in infants who developed BPD than in those who did not develop BPD. Increased CCSP oxidation and decreased immunoreactive CCSP expression in infants who subsequently developed BPD suggest that Clara cell function and CCSP expression may be critical for normal bronchoalveolar fluid homeostasis and that maintaining CCSP expression and function may be useful goals for targeted therapies for inhibition of the development of BPD.     

Urinary bombesin-like peptide levels in infants and children with bronchopulmonary dysplasia and cystic fibrosis

Compared to normal infants and children, there are increased numbers of neuroendocrine cells with bombesin-like peptide (BLP) immunostaining in the lungs of infants and children with bronchopulmonary dysplasia (BPD) and cystic fibrosis (CF). However, there are no data documenting levels of urinary BLP in normal infants and children, or in children with lung disease. We therefore determined the normal developmental pattern for urinary BLP excretion in healthy infants and children, and in infants and children with BPD and CF, and correlated these findings with the subjects' clinical course. We measured urinary BLP levels in 110 subjects: 54 controls, 33 with BPD, and 23 with CF. An age-dependent decline in urinary bombesin levels was evident in the control and BPD subjects, but not in those with CF. There were no statistically significant differences in BLP levels between normal infants and those with BPD. Mean BLP levels were higher in the more immature preterm infants with BPD who required increased ventilatory support. The highest mean BLP levels were documented in BPD infants under age 3 months (882 fmol/mg creatinine), in controls between 3 and 12 months of age (625 fmol/mg creatinine), and in 12–60-month-old CF subjects (486 fmol/mg creatinine). Thus there is an age-dependent decline in BLP levels in controls and BPD, but not in CF. We speculate that the elevated urinary BLP levels in infants and children with BPD and CF may reflect increased pulmonary neuroendocrine cell activity in these conditions, due to the epithelial regenerative response to airway damage and repair. Pediatr Pulmonol. 1998; 26:326–331. © 1998 Wiley-Liss, Inc.     

Soluble interleukin-2 receptor levels in infants with bronchopulmonary dysplasia.

Soluble interleukin-2 receptors (sIL2R) in plasma have been identified as a marker of lymphocyte activation. Lymphocyte activation as a manifestation of inflammation may be important in the pathogenesis of bronchopulmonary dysplasia (BPD). To test the hypothesis that infants with BPD have higher sIL2R levels, 12 infants with or at risk of developing BPD (GA +/- SD, 27 +/- 5 weeks; BW +/- SD 1,053 +/- 733 g) had plasma sIL2R levels determined and were compared to 20 infants being ventilated for respiratory distress syndrome (RDS) (GA +/- SD, 28 +/- 3.5 weeks; BW +/- SD, 1,133 +/- 390 g: P = NS for both GA and BW, t test). Tracheal aspirates in both groups were also analyzed for sIL2R levels. To control for the effects of postnatal age (PNA) and study weight (SW) on the sIL2R levels, another group of 16 nonventilated babies (NVB) had plasma analyzed for sIL2R (PNA +/- SD: 39 +/- 40 days NVB vs. 48 +/- 36 days BPD; P = NS); (SW +/- SD: 1391 +/- 250 g NVB vs. 1212 +/- 700 g BPD; P = NS). The following data were obtained for the plasma sIL2R levels (mean +/- SEM U/mL): RDS controls, 1,231 +/- 80; BPD infants, 1,790 +/- 120; NVB controls, 1,319 +/- 76; P = 0.0005 RDS vs. BPD and P = 0.002 BPD vs. NVB. There was no significant difference in the sIL2R levels for the infants at risk of developing BPD vs. the infants with established BPD. Also, when analyzed separately, infants at risk of BPD and the infants with established BPD had higher sIL2R levels than the RDS and NVB controls. No differences were noted in the tracheal sIL2R levels in the BPD vs. RDS groups. These data indicate that infants with BPD had significantly higher sIL2R levels in plasma than either RDS or NVB controls. Therefore, lymphocyte activation may play a role in the pathogenesis of BPD.     

Elevation of interleukin-8 and interleukin-6 precedes the influx of neutrophils in tracheal aspirates from preterm infants who develop bronchopulmonary dysplasia

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 lungs, or they are early markers of the inflammatory process that places preterm infants at high risk for BPD. Pediatr. Pulmonol. 1997; 24:331–336. © 1997 Wiley-Liss, Inc.     

Undernutrition as a major contributing factor in the pathogenesis of bronchopulmonary dysplasia

The protean effects of undernutrition on lung defenses and repair capabilities suggest that less than adequate nutritional support is a key pathogenetic factor in the development of bronchopulmonary dysplasia (BPD). Very-low-birthweight (VLBW, less than or equal to 1,000 g) premature infants who require intensive respiratory support have a distressingly high incidence of chronic lung disease or BPD. Many VLBW infants are currently undernourished during the most acute phase of their respiratory illness. Because VLBW newborns have only meager caloric reserves (fat, glycogen), and have only marginally sufficient stores of nutrients needed for effective lung defenses and repair capacity (vitamins A and E, copper, zinc, iron, selenium, essential fatty acids, etc.), the adequacy of nutritional support provided them will almost certainly influence their ability to tolerate early stress, and it may play a critical role in their clinical outcome. Experimental studies, combined with a limited number of clinical studies, clearly demonstrate that undernutrition can interact with each of the other well-accepted etiologic factors involved in the pathogenesis of BPD. Nutritional status affects the lung's ability to resist hyperoxic damage, to replace damaged/sloughed lung cells caused by barotrauma, to promote continued lung growth, to resist infection, and to tolerate prolonged and potentially toxic stresses in general. By providing more ideal nutritional support, clinicians may be able to apply preventive treatment to influence the outcome of intensive respiratory therapy in the VLBW newborn.     

Lung function following very preterm birth in the era of ‘new’ bronchopulmonary dysplasia

One of the most significant complications of preterm birth is bronchopulmonary dysplasia (BPD). The pathophysiology of BPD has changed in recent years as advances in neonatal care have led to increased survival of smaller, more preterm, infants who display alterations to alveolar and pulmonary microvascular development. It is becoming clear that infants with ‘new’ BPD experience lung disease that persists into later childhood, however, the oldest of these children are just now entering young adulthood and therefore the longer term pulmonary implications remain unknown. The role of lung function testing in the identification and subsequent management of patients with lung disease resulting from a neonatal classification of BPD is reviewed based on the underlying pathophysiology of the disease.     

Effect of sleep state on chest wall movements and gas exchange in infants with resolving bronchopulmonary dysplasia

During active sleep, neonates exhibit asynchronous chest wall movements, which have been associated with a small but significant decrease in oxygenation. To determine the effects of maturation and residual chronic lung disease on both these phenomena, we studied 11 preterm infants with resolving bronchopulmonary dysplasia (BPD) and compared these infants to ten healthy preterm infants all at time of discharge. Synchrony of chest wall (upper rib cage and abdominal) movements, sleep state, O2 saturation, and transcutaneous CO2 (TcPCO2) were recorded during both active (AS) and quiet sleep (QS). Sleep state was determined by electroencephalographic and behavioral criteria. Normal preterm infants displayed asynchronous chest wall movements only in AS, whereas, in infants with BPD, asynchrony predominated in both sleep states, although O2 saturation and TcPCO2 did not differ between sleep states in either group. The O2 saturation during AS was lower in the BPD group than in the group of normal infants (92% vs 96%; P less than 0.02), whereas TcPCO2 was higher in the BPD group unrelated to sleep state. We conclude that infants with resolving BPD exhibit asynchronous chest wall movements in both AS and QS, and that change in sleep state from QS to AS is not associated with a detrimental fall in oxygenation in these infants.     

Prevention and Treatment of Bronchopulmonary Dysplasia: Contemporary Status and Future Outlook

Despite tremendous advances in neonatology, bronchopulmonary dysplasia (BPD) remains a major cause of morbidity and mortality among premature infants. Any intervention that would reduce the risk of BPD or improve its outcome is likely to have substantial clinical and financial benefits. However, there is a clear lack of an effective agent for the treatment and/or prevention of BPD. This is due to an incomplete understanding of the molecular mechanisms involved in its pathogenesis. Taking a basic biological approach, our laboratory has discovered that disruption of normal alveolar homeostatic signaling is centrally involved in this process. Using a number of in vitro and in vivo models, our laboratory has demonstrated that stabilization of the normal alveolar homeostatic signaling pathway(s) can prevent and/or rescue the molecular injuries caused by the insults that lead to BPD. Here, we review the existing approaches to prevent and treat BPD and then, based on our insights into the pathogenesis of BPD, we propose novel and innovative therapeutic options that impact the disease on a cell/molecular level, unlike most of the current treatments available for BPD.     

Long-term respiratory outcome of babies born prematurely

Chronic respiratory morbidity is a common adverse outcome of premature birth, particularly in infants who develop bronchopulmonary dysplasia (BPD). Prematurely born infants who had BPD may require supplementary oxygen at home for many months, but few remain oxygen dependent beyond 2 years of age. Readmission to hospital is common, particularly for those who had BPD, but only in the first 2 years after birth. The readmissions are usually for respiratory problems, particularly respiratory syncytial virus lower respiratory infections. Recurrent respiratory symptoms requiring treatment are common, particularly in those who had BPD, even at school age and in adolescence. Affected children have evidence of airways obstruction. Pulmonary function does improve with age, but children with BPD may have ongoing airflow limitation. Computed tomography of the chest gives helpful information at follow up of patients with ongoing respiratory problems who had BPD.     

Pulmonary vascular extraction of circulating norepinephrine in infants with bronchopulmonary dysplasia

Although the pulmonary circulation in infants with advanced bronchopulmonary dysplasia (BPD) is characterized by abnormal structure and vasoreactivity, metabolic lung functions have not been studied in these infants. To test the hypothesis that patients with severe BPD may have abnormal metabolic lung function, we assessed the pulmonary vascular extraction of circulating norepinephrine in six children with BPD during cardiac catheterization. Plasma norepinephrine levels were measured from simultaneously drawn mixed venous (main pulmonary artery) and left atrium or femoral artery samples. In comparison with four infants with mild heart disease without pulmonary hypertension, we found that infants with BPD extract proportionately less norepinephrine than non-BPD infants [-7 +/- 50% (BPD) versus +27 +/- 6% (non-BPD); P less than 0.001, t test]. Three infants with BPD had higher arterial than mixed venous concentrations of plasma norepinephrine, suggesting net production across the lung. Plasma catecholamine levels and percent extraction correlated poorly with cardiac index and systemic and pulmonary vascular resistance indices. However, this study group was characterized by a high incidence of pulmonary (6/6) and systemic (4/6) hypertension, left ventricular hypertrophy (4/6), and subsequent death (3/6). We conclude that infants with severe BPD and pulmonary hypertension have decreased pulmonary vascular clearance or net production of circulating norepinephrine, but links between altered pulmonary catecholamine metabolism and pulmonary hypertension, or other cardiovascular abnormalities associated with BPD, remain speculative.