Chronic Bronchopulmonary Dysplasia Research Articles

An Experimental Model of Bronchopulmonary Dysplasia Features Long-Term Retinal and Pulmonary Defects but Not Sustained Lung Inflammation.

Bronchopulmonary dysplasia (BPD) is a severe lung disease that affects preterm infants receiving oxygen therapy. No standardized, clinically-relevant BPD model exists, hampering efforts to understand and treat this disease. This study aimed to evaluate and confirm a candidate model of acute and chronic BPD, based on exposure of neonatal mice to a high oxygen environment during key lung developmental stages affected in preterm infants with BPD. Neonatal C57BL/6 mouse pups were exposed to 75% oxygen from postnatal day (PN)-1 for 5, 8, or 14 days, and their lungs were examined at PN14 and PN40. While all mice showed some degree of lung damage, mice exposed to hyperoxia for 8 or 14 days exhibited the greatest septal wall thickening and airspace enlargement. Furthermore, when assessed at PN40, mice exposed for 8 or 14 days to supplemental oxygen exhibited augmented septal wall thickness and emphysema, with the severity increased with the longer exposure, which translated into a decline in respiratory function at PN80 in the 14-day model. In addition to this, mice exposed to hyperoxia for 8 days showed significant expansion of alveolar epithelial type II cells as well as the greatest fibrosis when assessed at PN40 suggesting a healing response, which was not seen in mice exposed to high oxygen for a longer period. While evidence of lung inflammation was apparent at PN14, chronic inflammation was absent from all three models. Finally, exposure to high oxygen for 14 days also induced concurrent outer retinal degeneration. This study shows that early postnatal exposure to high oxygen generates hallmark acute and chronic pathologies in mice that highlights its use as a translational model of BPD.

VITAMIN E IN THE PREVENTION OF CHRONIC BRONCHOPULMONARY DYSPLASIA IN LOW BIRTH WEIGHTINFANTS

Journal Article Vitamin E in the Prevention of Chronic Bronchopulmonary Dysplasia in Low Birth Weight Infants Get access Nutrition Reviews, Volume 37, Issue 1, January 1979, Pages 11–12, https://doi.org/10.1111/j.1753-4887.1979.tb02187.x Published: 01 January 1979

Asthmaprädiktoren - Prognose der obstruktiven Bronchitis im frühen Kindesalter

The aim of the study was to check and analyse the long-term outcome of infants and toddlers suffering from frequently relapsing and/or (with airway obstruction) and to find prognostic factors. Methods: We observed and analysed the clinical outcome for 2-7 years in 115 children (31 infants/babies and 84 toddlers) suffering from obstructiva recidivans and/or obstructiva chronica in a prospective study. A multivariate analysis was made for the factors disease in other family members/FA, infection of the sex of the patient, associated atopic diseases of the child/patient, the IgE serum (IgE) of the child/patient, chronic bronchopulmonary dysplasia of former pretem infants/bpD, pathological gastroesophageal reflux/GER, significantly secretory eosinophilia/SSE in nasal or bronchial secretion smears (> 13% eosinophils), the concentration of the eosinophilic cationic protein (ECP concentration) of serum and tracheobronchial secretions (TBA). Results: 2/3 of all children became healthy at the end of the study but 1/3 of the infants/toddlers developed a typical bronchial asthma. The FA, associated atopic diseases of the child/patient, the and total serum IgE level of the child/patient could be identified as positive predicting factors for the development of bronchial asthma and had a sensitivity of 50-90% and a specifity of 76-91%. The prognostic values of these 4 factors were increasing from 44-57% (only a single factor was existing) up to 64-91% (in two factors) and finally to 89-100% in 3 and/or 4 factors. Conclusions: In contrast to the literature we found, that the early RSV infection, GER, bpD and ECP of serum and TBA had no statistical link to the development of bronchial asthma in childhood. In young children suffering from frequently relapsing or the following signs have a predictive/prognostic value: Atopic diseases in other family members (FA), other atopic diseases of the child, SSE and elevated serum IgE of the child/patient. These factors indicate that the child's early bronchitis has a poor long-term prognosis and will become a bronchial asthma.

Localization and potential role of matrix metalloproteinase-1 and tissue inhibitors of metalloproteinase-1 and -2 in different phases of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) can evolve in prematurely born infants who require mechanical ventilation because of hyaline membrane disease (HMD). The development of BPD can be divided in an acute, a regenerative, a transitional, and a chronic phase. During these different phases, extensive remodeling of the lung parenchyma with re-epithelialization of the alveoli and formation of fibrosis occurs. Matrix metalloproteinase-1 (MMP-1) is an enzyme that is involved in re-epithelialization processes, and dysregulation of MMP-1 activity contributes to fibrosis. Localization of MMP-1 and its inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, were investigated in lung tissue obtained from infants who died during different phases of BPD development. In all studied cases (n = 50) type-II pneumocytes were found to be immunoreactive for MMP-1, TIMP-1, and TIMP-2. During the acute and regenerative phase of BPD, type-II pneumocytes re-epithelialize the injured alveoli. This may suggest that MMP-1 and its inhibitors, expressed by type-II pneumocytes, play a role in the re-epithelialization process after acute lung injury. Although MMP-1 staining intensity remained constant in type-II pneumocytes during BPD development, TIMP-1 increased during the chronic fibrotic phase. This relative elevation of TIMP-1 compared with MMP-1 is indicative for reduced collagenolytic activity by type-II pneumocytes in chronic BPD and may contribute to fibrosis. Fibrotic foci in chronic BPD contained fibroblasts immunoreactive for MMP-1 and TIMP-1 and -2. This may indicate that decreased collagen turnover by fibroblasts contributes to fibrosis in BPD development.

Preterm infants with high polyunsaturated fatty acid and plasmalogen content in tracheal aspirates develop bronchopulmonary dysplasia less often

Oxygen toxicity causes chronic bronchopulmonary dysplasia (BPD) in extremely preterm infants. Polyunsaturated fatty acids (PUFA) and plasmalogens are the two main substrates for lipid peroxidation in the pulmonary surfactant. In the present study, we tested whether low concentrations of both were associated with development of BPD and whether both were further reduced during mechanical ventilation with oxygen. Prospective, noninterventional, descriptive study. Level III neonatal intensive care unit in a university hospital. In 25 extremely low birth weight infants with respiratory distress syndrome, tracheal aspirates were collected immediately after birth and in the following 4 days. As control, tracheal and pharyngeal aspirates were collected from healthy infants immediately after birth. The amount of PUFA and dimethylacetals (DMA, representing plasmalogens) was determined gas-chromatographically. None. The relative percentages of PUFA and DMA on all fatty acids in non-BPD infants (PUFA% 26+/-8.9, DMA% 3.5+/-1.2) were higher compared with infants who developed BPD (PUFA% 14.5+/-3.8, DMA% 1.8+/-0.9). In term healthy infants, DMA% and PUFA% were in the same range as in the BPD group. The higher levels found for non-BPD infants decreased after day 1 to values equal to the BPD group and remained low. The results suggest that initially higher levels of PUFA and plasmalogens in the tracheal effluent are associated with a reduced risk of developing BPD and are reduced during the first day of ventilation.

Early transfer to a rehabilitation hospital for infants with chronic bronchopulmonary dysplasia.

Shortly after being weaned off the respirator, 43 infants with severe chronic bronchopulmonary dysplasia (BPD) were transferred from an intensive-care nursery at a teaching hospital to an affiliated children's rehabilitation hospital in a program that included special staff instruction. Morbidity, measured by rate of transfer back to the acute-care hospital, was lower than in a comparison group of 15 infants treated for severe BPD during the previous two years. Average length of stay was significantly shortened and an average of $60,000 per patient was saved. Using a rehabilitation hospital as a step-down unit shifts the emphasis from acute needs to chronic and developmental needs and from intensive monitoring and nursing care to care given at home by parents with nursing assistance.

Double-blind, placebo-controlled trial of alternate-day furosemide therapy in infants with chronic bronchopulmonary dysplasia

To test the hypothesis that alternate-day administration of furosemide will result in a sustained improvement in pulmonary function without causing alterations in electrolyte or mineral homeostasis, we conducted a randomized, double-blind, placebo-controlled study of 11 hospitalized, oxygen-dependent, spontaneously breathing infants with chronic bronchopulmonary dysplasia. Infants were randomly selected to receive either furosemide, 4 mg/kg in two divided doses on alternate days orally, or placebo for 8 days, followed by crossover to the alternate-therapy for an additional 8-day period. The two study periods were separated by a 48-hour washout period. Dynamic compliance, total pulmonary resistance, the concentration of electrolytes in serum, and the concentrations of calcium and creatinine in urine were measured on nontreatment days. Alternate-day furosemide therapy increased dynamic lung compliance by 76 +/- 112% and decreased total pulmonary resistance by 20 +/- 39%, compared with placebo (both variables p = 0.032). Alternate-day furosemide therapy did not result in increased urine output, electrolyte abnormalities, or increased urinary calcium excretion. We conclude that this simplified treatment regimen may be useful in the management of infants with chronic bronchopulmonary dysplasia. The results support our previous speculation that furosemide improves pulmonary function by mechanisms unrelated to its diuretic properties.

Hemoglobin Oxygen Dissociation (P<sub>50</sub>) in Bronchopulmonary Dysplasia

A study was devised to determine the P50 in infants with bronchopulmonary dysplasia (BPD). Other factors such as red blood cell 2,3-diphosphoglycerate (2,3-DPG) level proportions of adult (HbA) to fetal (HbF) hemoglobins which could affect P50 were also measured. Fourteen infants with clinical and radiological signs of BPD with a mean post-conceptional age of 42.2 +/- 4.7 weeks born at a mean gestational age of 29.3 +/- 2.0 weeks were evaluated. The percentage of HbF determined in 8 infants was 40.1 +/- 20.3% and the mean 2,3-DPG concentrations was 13.1 +/- 2.2 mumol/g Hb. The P50 was 25.1 +/- 2.7 mm Hg (range 18-29.5 mm Hg). When a HbO2 curve was established based on a large volume of blood consisting of adult blood and newborn cord blood mixed to attain a P50 of 25.1 mm Hg, the PaO2 at 90% O2 saturation was 52 mm Hg. Since there can be a wide range in HbO2 in infants with chronic BPD, pulse oximetry remains the most prudent method of monitoring oxygen therapy in BPD infants.

Effect of spironolactone-hydrochlorothiazide on lung function in infants with chronic bronchopulmonary dysplasia

To test the hypothesis that spironolactone-hydrochlorothiazide (Aldactazide) will improve urine output and lung function in infants with bronchopulmonary dysplasia, we studied 21 hospitalized, spontaneously breathing, oxygen-dependent infants with chronic bronchopulmonary dysplasia. Infants were randomly assigned to receive either a 1:1 mixture of spironolactone and hydrochlorothiazide orally (n = 12) (3 mg/kg/day of both compounds) or no treatment (n = 9) for 6 to 8 days each. Dynamic lung compliance, total pulmonary resistance, and hemoglobin oxygen saturation were measured on the first and last days of each study period. Fluid intake and urine output were measured each day. Although the treatment significantly increased urine output, neither lung mechanics nor oxygenation were improved by the drug. The magnitude of the diuresis achieved with spironolactone-hydrochlorothiazide treatment was comparable to the diuresis achieved in a previous study of furosemide treatment (J Pediatr 1986:109;1034-9). Statistical analysis indicated that a type II error was an unlikely explanation for our failure to detect a beneficial effect. In three patients, doubling the oral dose did not improve lung mechanics or oxygenation. We speculate that diuresis per se is not responsible for lung function improvement during treatment with other drugs with diuretic properties.

Control of water balance in infants with bronchopulmonary dysplasia: role of endogenous vasopressin.

Babies with chronic bronchopulmonary dysplasia (BPD) can sometimes develop pallor, systemic and pulmonary edema, oliguria, and hyponatremia not attributable to cardiopulmonary or renal impairment. These signs and symptoms might, however, be explained by inappropriate control of vasopressin secretion. To test this hypothesis, we measured plasma vasopressin and osmolality, serum sodium and potassium concentrations, urine output and osmolality, and free water clearance in 26 normoxic infants with BPD aged 1-4 months. All of these infants required supplemental oxygen (FiO2 0.41 +/- 0.03, mean +/- 1 SE) to maintain O2 saturation of greater than 88%, and six infants also required mechanical ventilation. As controls, 10 infants of similar age but without BPD were also studied. None of the infants had been discharged from the nursery and was receiving any medications, and all were clinically stable when studied. Compared to control infants, infants with BPD had significantly elevated plasma vasopressin concentrations (control 5.2 +/- 0.9 pg/ml; BPD 42.4 +/- 5.1; mean +/- SE, p less than 0.05). Moreover, infants with BPD had hyponatremia and hypotonic plasma, and both urine output and free water clearance were significantly reduced. These data suggest that some infants with chronic BPD have elevated vasopressin levels that are functionally significant. We speculate that excessive stimulation of vasopressin secretion may explain some of the pulmonary and nonpulmonary signs and symptoms in infants with chronic BPD.

Flat chest in chronic bronchopulmonary dysplasia.

In patients with chronic bronchopulmonary dysplasia, the anteroposterior dimension of the chest on the lateral radiograph is often relatively narrow compared with the chest width on the frontal radiograph. A prospective comparison was made of pediatric clinic outpatients who had chest radiography during a 1-month period. Chest widths and thicknesses were measured from the anteroposterior and lateral radiographs, respectively, and a dimensionless ratio of width to thickness was calculated. The chest thus measured was significantly flatter (p less than 10(-6] in 18 patients with chronic bronchopulmonary dysplasia than it was in 128 unaffected patients and in 18 unaffected age-matched patients; there was, however, considerable overlap in chest dimensions between patients with and without bronchopulmonary dysplasia. We speculate that the abnormality results from a combination of demineralized bones, prolonged recumbent positioning, and chronic sternal retraction. It is plausible, but remains to be proved, that this chest wall deformity may be clinically deleterious because it interferes with respiratory mechanics. This prospective comparison of patients with and without bronchopulmonary dysplasia shows that despite considerable overlap in chest dimensions, patients with bronchopulmonary dysplasia tend to have a distinctive chest deformity whose measured difference from control patients is statistically significant.

Effect of Oral Diuretics on Pulmonary Mechanics in Infants with Chronic Bronchopulmonary Dysplasia: Results of a Double-Blind Crossover Sequential Trial

In a randomized double-blind crossover trial with sequential analysis, the effects of oral diuretics were compared with the effects of placebo on pulmonary mechanics in ten infants with bronchopulmonary dysplasia (BPD). Pulmonary mechanics were measured before and at the end of a week of treatment with oral diuretics (chlorothiazide, 20 mg/kg/dose and spironolactone, 1.5 mg/kg/dose) given twice daily, or placebo. Mean airway resistance decreased 35.3 cm H2O/L/s, mean specific airway conductance increased 0.095 1/L/s/cm H2O, and mean dynamic pulmonary compliance increased 1.74 mL/cm H2O during treatment with diuretics (all P less than .001), but not during treatment with placebo. The infants' rate of weight gain decreased on the first three days of diuretic treatment, but was thereafter comparable with weight gain during treatment with placebo. Fluid intake was similar in infants receiving diuretics and placebo. But, infants receiving diuretics not only had significantly increased urine output, osmolal clearance, and potassium and phosphorus excretion, but these infants also retained less fluid, and, in addition, excreted less calcium than infants receiving placebo. It is concluded that oral diuretics improve lung function in infants with chronic bronchopulmonary dysplasia; however, potassium and phosphorus depletion are potential complications of treatment.

Furosemide acutely decreases airways resistance in chronic bronchopulmonary dysplasia

We studied the effects of furosemide on pulmonary mechanics in 10 infants with bronchopulmonary dysplasia aged 41 +/- 1 (SE) weeks post-conception, gestational age at birth 30 +/- 1 wk, birth weight 1370 +/- 200 gm. Thoracic gas volume, airways resistance, and specific airway conductance were measured in an infant body pressure plethysmograph during quiet breathing. Dynamic pulmonary compliance was measured using an esophageal balloon. Infants with BPD had greater Raw, lower SGaw, and lower Cdyn than did 16 normal control infants. Within one hour after administration of furosemide 1 mg/kg IV to infants with BPD, Raw fell 36 +/- 13%, SGaw increased 84 +/- 22%, and Cdyn increased 54 +/- 13%; TGV did not change. Diuretic treatment of BPD in infants is associated with rapid, short-term improvement in Raw and Cdyn.

Pulmonary neuroendocrine cells in hyaline membrane disease and bronchopulmonary dysplasia.

The number and distribution of bombesin immunoreactive pulmonary neuroendocrine cells (PNEC) in fetuses and infants up to 6 months of age was determined on postmortem lung specimens. Individual cells and clusters of cells (neuroepithelial bodies) were found in airways of all sizes, although greater than 95% of the positive cells were located in bronchioles, terminal bronchioles, and respiratory bronchioles. These infants were separated into two groups. In control infants, who died primarily from noncardiopulmonary causes, bombesin immunoreactive neuroendocrine cells were identified throughout the latter half of gestation. As gestation advanced, progressively more positive bronchioles/cm2 of lung tissue and cells/bronchiole were identified. In these control infants, the number of positive bronchioles/cm2 and cells/bronchiole were at the highest level at or near the time of delivery and then gradually declined throughout the first 6 months of life. In contrast, infants who died of acute hyaline membrane disease (1-7 days of life) or bronchiopulmonary dysplasia (2 wk to 6 months of life) demonstrated marked differences in the number of identifiable bombesin immunoreactive neuroendocrine cells when compared to control infants. In early hyaline membrane disease, the number of positive bronchioles/cm2 and cells/bronchiole was markedly decreased. During the transition to chronic bronchopulmonary dysplasia, there appeared to be a marked increase in the number of bombesin immunoreactive cells. The peak number of cells occurred at 2-3 months of life, when substantially more bombesin-immunoreactive cells could be identified in children with bronchopulmonary dysplasia than control infants of similar age.

Abnormal Lung Surfactant Related to Essential Fatty Acid Deficiency in a Neonate

A low-birth-weight infant, suffering from chronic bronchopulmonary dysplasia following hyaline membrane disease and recurrent episodes of necrotizing enterocolitis, developed biochemical evidence of essential fatty acid (EFA) deficiency in the plasma. Fatty acid composition of phosphatidylcholine and phosphatidylglycerol in the lung lavage fluid was abnormal. Plasma changes included a decrease in the level of linoleic acid and an increased level of palmitic, palmitoleic, oleic, and 5,8,11-eicosatrienoic acid to arachidonic acid being greater than 0.4:1. A lower than normal level of palmitic acid and an increased level of palmitoleic and oleic acids were seen in pulmonary sufactant phospholipid components. Upon treatment and recovery from EFA deficiency, the fatty acid pattern both in plasma and surfactant phospholipids returned to normal along with clinical improvement. An association between EFA deficiency and altered fatty acid composition of pulmonary surfactant phospholipids is suggested.

Urinary excretion of prostaglandin E following the administration of furosemide and indomethacin to sick low-birth-weight infants

Urinary excretion of prostaglandin E was measured in seven sick low-birth-weight infants. Four had severe hyaline membrane disease and one had chronic bronchopulmonary dysplasia; all received furosemide. Two infants had patent ductus arteriosus and received indomethacin. Following administration of furosemide, urine volume and the excretion rates of sodium and calcium were significantly increased; such changes were not seen following the administration of indomethacin. Prostaglandin E excretion rate was increased from 0.4 +/- 0.04 to 1.3 +/- 0.2 ng/mg Cr (mean +/- SEM) following administration of furosemide, but decreased in two patients following administration of indomethacin. The present results demonstrate that furosemide enhances urinary excretion of prostaglandin E by mechanisms which may reflect an increase in prostaglandin synthesis, a decrease in prostaglandin renal metabolism, or both. Indomethacin, which is a prostaglandin synthetase inhibitor, decreases the urinary excretion of prostaglandin E. These observations suggest that furosemide therapy in patients receiving indomethacin may be ineffective.

103 URINARY EXCRETION OF PROSTAGLANDIN E FOLLOWING THE ADMINISTRATION OF FUROSEMIDE AND INDOMETHACIN TO SICK LOW BIRTHUEIGHT INFANTS

Urinary excretion of prostaglandin E was measured in seven sick low birthweight infants. Four had severe hyaline membrane disease, one had chronic bronchopulmonary dysplasia and all received furosemide. Two infants suffered from patent ductus arteriosus and received indomethacin. Urinary volume and the excretion of sodium, calcium and prostaglandin E were determined in these infants before and after the administration of these drugs. Following furosemide administration, urine volume and the excretion rates of sodium and calcium were significantly increased; such changes were not seen following the administration of indomethacin. Prostaglandin E excretion rate was increased from 0.4 ± 0.04 to 1.3 ± 0.2 ng/mg Cr (mean ± SEM) following furosemide administration but decreased from 1.0 to 0.4 (mean) ng/mg Cr following indomethacin administration. The mechanism(s) by which furosemide enhances urinary excretion of prostaglandin E may be an increase in prostaglandin synthesis, a decrease in their renal metabolism or both. However, indomethacin which is a prostaglandin synthetase inhibitor, decreases the urinary excretion of prostaglandin E in a dose-dependent fashion. These observations suggest the possibility that in patients receiving indomethacin furosemide therapy may be ineffective.