Search

Objective: To explore clinical effect modifiers of systemic hydrocortisone in ventilated very preterm infants for survival and neurodevelopmental outcome at 2 years' corrected age (CA)., Design: Secondary analysis of a randomised placebo-controlled trial., Setting: Dutch and Belgian neonatal intensive care units., Patients: Infants born <30 weeks' gestational age (GA), ventilator-dependent in the second week of postnatal life., Intervention: Infants were randomly assigned to systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190)., Main Outcome Measures: The composite of death or neurodevelopmental impairment (NDI) at 2 years' CA and its components. Candidate effect modifiers (GA, small for GA, respiratory index, sex, multiple births, risk of moderate/severe bronchopulmonary dysplasia or death) were analysed using regression models with interaction terms and subpopulation treatment effect pattern plots., Results: The composite outcome was available in 356 (96.0%) of 371 patients (one consent withdrawn). For this outcome, treatment effect heterogeneity was seen across GA subgroups (<27 weeks: hydrocortisone (n=141) vs placebo (n=156), 54.6% vs 66.2%; OR 0.61 (95% CI 0.38 to 0.98); ≥27 weeks: hydrocortisone (n=30) vs placebo (n=31), 66.7% vs 45.2%; OR 2.43 (95% CI 0.86 to 6.85); p=0.02 for interaction). This effect was also found for the component death (<27 weeks: 20.1% vs 32.1%; OR 0.53 (95% CI 0.32 to 0.90); ≥27 weeks: 28.1% vs 16.1%; OR 2.04 (95% CI 0.60 to 6.95); p=0.049 for interaction) but not for the component NDI. No differential treatment effects were observed across other subgroups., Conclusion: This secondary analysis suggests that in infants <27 weeks' GA, systemic hydrocortisone may improve the outcome death or NDI, mainly driven by its component death. There was insufficient evidence for other selected candidate effect modifiers., Competing Interests: Competing interests: AHvK reports grants from the Netherlands Organization for Health Research and Development (ZonMW) during the conduct of the study. No other disclosures were reported., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The past decades have seen markedly improved survival of increasingly immature preterm infants, yet major health complications persist. This is particularly true for bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, which has become the most common sequelae of prematurity and a significant predictor of respiratory morbidity throughout childhood as well as adult life, neurodevelopmental disability, cardiovascular disease, and even death. The need for novel approaches to reduce BPD and related complications of prematurity has never been more critical. Thus, despite major advances in the use of antenatal steroids, surfactant therapy, and improvements in respiratory support, there is a persistent need for developing therapeutic strategies that more specifically reflect our growing understanding of BPD in the post-surfactant age, or the "new BPD." In contrast with the severe lung injury leading to marked fibroproliferative disease from the past, the "new BPD" is primarily characterized by an arrest of lung development as related to more extreme prematurity. This distinction and the continued high incidence of BPD and related sequelae suggest the need to identify therapies that target critical mechanisms that support lung growth and maturation in conjunction with treatments to improve respiratory outcomes across the lifespan. As the prevention of BPD and its severity remains a primary goal, we highlight the concept from preclinical and early clinical observations that insulin-like growth factor 1 (IGF-1) can potentially support the natural sequence of lung growth as a replacement therapy after preterm birth. Data supporting this hypothesis are robust and include observations that low IGF-1 levels persist after extremely preterm birth in human infants and strong preclinical data from experimental models of BPD highlight the therapeutic benefit of IGF-1 in reducing disease. Importantly, phase 2a clinical data in extremely premature infants where replacement of IGF-1 with a human recombinant human IGF-1 complexed with its main IGF-1 binding protein 3, significantly reduced the most severe form of BPD, which is strongly associated with multiple morbidities that have lifelong consequences. As physiologic replacement therapy of surfactant heralded the success of reducing acute respiratory distress syndrome in preterm infants, the paradigm has the potential to become the platform for discovering the next generation of therapies like IGF-1, which becomes deficient after extremely premature birth where endogenous production by the infant is not sufficient to maintain the physiologic levels adequate to support normal organ development and maturation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Niklas is CMO of Oak Hill Bio and owns shares. Dr. Abman is scientific advisor to Oak Hill Bio., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Bronchopulmonary dysplasia (BPD) and poor neurodevelopmental outcome after preterm birth are closely associated. However, mechanistic links are uncertain. We are exploring the hypothesis that decreased circulating insulin-like growth factor (IGF)-1 after preterm birth due to the abrupt end of supply by the placenta impairs growth during critical windows of development in most organs, including the lung and brain. Throughout gestation, the fetus uses glycolysis as its main source of energy. Metabolism is mainly stopped at pyruvate, which serves as a "metabolic crossroad", allowing for the production of amino acids and other "building blocks" for new cells. Metabolic pathways are differentially regulated in the nucleus and the cytoplasm. The ratio between pyruvate dehydrogenase (PDH) and pyruvate dehydrogenase kinase (PDK) determines the biochemical activity which irreversibly metabolizes pyruvate to acetyl-co-A. Metabolites in the nucleus modulate epigenetic remodeling, an essential mechanism of normal growth and maturation during development. IGF-1 has been shown to contribute significantly to the development of virtually all organs, especially related to the regulation of microvascular growth, based on extensive studies of the brain, retina, lung, and intestine. With a preterm birth, the abrupt withdrawal of the placental supply of IGF-1 and its local production directly affects metabolism and microvascular development, which may contribute to a high risk for organ maldevelopment and injury after birth. We speculate that reduced bioavailability of IGF-1 is a possible link between lung and brain development disruption and increases susceptibility for major pulmonary and neurocognitive morbidities in preterm babies. KEY POINTS: · Metabolic changes inherent to prterm birth may cause epigenetic changes which cause "dysmaturational" development.. · IGF-1 may be the potential link between BPD and brain development.. · The ratio between pyruvate dehydrogenase and pyruvate dehydrogenase kinase determines the biochemical activity.., Competing Interests: V.N. is a shareholder and employee of Oak Hill Bio, actively developing mecasermin rinfibate (recombinant human IGF-1/binding protein complex 3); S.A. is a member of Oak Hill Bio scientific advisory board., (Thieme. All rights reserved.)

Background: The addition of budesonide (Bud) 0.25 mg/kg to surfactant decreased the lung and systemic responses to mechanical ventilation in preterm sheep and the rates and severity of bronchopulmonary dysplasia (BPD) in preterm infants. We hypothesized that lower budesonide concentrations in surfactant will decrease injury while decreasing systemic corticosteroid exposure., Methods: Preterm lambs received either (1) protective tidal volume (V T ) ventilation with surfactant from birth or (2) injurious V T ventilation for 15 min and then surfactant treatment. Lambs were further assigned to surfactant mixed with (i) Saline, (ii) Bud 0.25 mg/kg, (iii) Bud 0.1 mg/kg, or (iv) Bud 0.04 mg/kg. All lambs were then ventilated with protective V T for 6 h., Results: Plasma Bud levels were proportional to the dose received and decreased throughout ventilation. In both protective and injurious V T ventilation, <4% of Bud remained in the lung at 6 h. Some of the improvements in physiology and markers of injury with Bud 0.25 mg/kg were also found with 0.1 mg/kg, whereas 0.04 mg/kg had only minimal effects., Conclusions: Lower doses of Bud were less effective at decreasing lung and systemic inflammation from mechanical ventilation. The plasma Bud levels were proportional to dose given and the majority left the lung.

Background: Treatment of bronchopulmonary dysplasia in preterm infants is challenging due to its multifactorial origin. In rodent models of neonatal lung injury, selective inhibition of phosphodiesterase 4 (PDE4) has been shown to exert anti-inflammatory properties in the lung. We hypothesized that GSK256066, a highly selective, inhalable PDE4 inhibitor, would have beneficial effects on lung injury and inflammation in a triple hit lamb model of Ureaplasma parvum (UP)-induced chorioamnionitis, prematurity, and mechanical ventilation. Methods: Twenty-one preterm lambs were surgically delivered preterm at 129 days after 7 days intrauterine exposure to UP. Sixteen animals were subsequently ventilated for 24 hours and received endotracheal surfactant and intravenous caffeine citrate. Ten animals were randomized to receive twice a high (10 μg/kg) or low dose (1 μg/kg) of nebulized PDE4 inhibitor. Results: Nebulization of high, but not low, doses of PDE4 inhibitor led to a significant decrease in pulmonary PDE activity, and was associated with lung injury and vasculitis, influx of neutrophils, and increased proinflammatory cytokine messenger RNA levels. Conclusion: Contrary to our hypothesis, we found in our model a dose-dependent proinflammatory effect of an inhaled highly selective PDE4 inhibitor in the lung. Our findings indicate the narrow therapeutic range of inhaled PDE4 inhibitors in the preterm population.

Importance: Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, remains one of the major and most common complications of very preterm birth. Insight into factors associated with the pathogenesis of BPD is key to improving its prevention and treatment., Objective: To perform a systematic review, meta-analysis, and metaregression of clinical studies exploring the association between chorioamnionitis (CA) and BPD in preterm infants., Data Sources: PubMed and Embase were searched without language restriction (last search, October 1, 2018). Key search terms included bronchopulmonary dysplasia, chorioamnionitis, and risk factors., Study Selection: Included studies were peer-reviewed studies examining preterm (<37 weeks' gestation) or very low-birth-weight (<1500 g) infants and reporting primary data that could be used to measure the association between exposure to CA and the development of BPD., Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline was followed. Data were independently extracted by 2 researchers. A random-effects model was used to calculate odds ratios (ORs) and 95% CIs. Heterogeneity in effect size across studies was studied using multivariate, random-effects metaregression analysis., Main Outcomes and Measures: The primary outcome was BPD, defined as supplemental oxygen requirement on postnatal day 28 (BPD28) or at the postmenstrual age of 36 weeks (BPD36). Covariates considered as potential confounders included differences between CA-exposed and CA-unexposed infants in gestational age, rates of respiratory distress syndrome (RDS), exposure to antenatal corticosteroids, and rates of early- and late-onset sepsis., Results: A total of 3170 potentially relevant studies were found, of which 158 met the inclusion criteria (244 096 preterm infants, 20 971 CA cases, and 24 335 BPD cases). Meta-analysis showed that CA exposure was significantly associated with BPD28 (65 studies; OR, 2.32; 95% CI, 1.88-2.86; P < .001; heterogeneity: I2 = 84%; P < .001) and BPD36 (108 studies; OR, 1.29; 95% CI, 1.17-1.42; P < .001; heterogeneity: I2 = 63%; P < .001). The association between CA and BPD remained significant for both clinical and histologic CA. In addition, significant differences were found between CA-exposed and CA-unexposed infants in gestational age, birth weight, odds of being small for gestational age, exposure to antenatal corticosteroids, and early- and late-onset sepsis. Chorioamnionitis was not significantly associated with RDS (48 studies; OR, 1.10; 95% CI, 0.92-1.34; P = .24; heterogeneity: I2 = 90%; P < .001), but multivariate metaregression analysis with backward elimination revealed that a model combining the difference in gestational age and the odds of RDS was associated with 64% of the variance in the association between CA and BPD36 across studies., Conclusions and Relevance: The results of this study confirm that among preterm infants, exposure to CA is associated with a higher risk of developing BPD, but this association may be modulated by gestational age and risk of RDS.

Importance: Dexamethasone initiated after the first week of life reduces the rate of death or bronchopulmonary dysplasia (BPD) but may cause long-term adverse effects in very preterm infants. Hydrocortisone is increasingly used as an alternative, but evidence supporting its efficacy and safety is lacking., Objective: To assess the effect of hydrocortisone initiated between 7 and 14 days after birth on death or BPD in very preterm infants., Design, Setting, and Participants: Double-blind, placebo-controlled randomized trial conducted in 19 neonatal intensive care units in the Netherlands and Belgium from November 15, 2011, to December 23, 2016, among preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1250 g who were ventilator dependent between 7 and 14 days of life, with follow-up to hospital discharge ending December 12, 2017., Interventions: Infants were randomly assigned to receive a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (n = 182) or placebo (n = 190)., Main Outcomes and Measures: The primary outcome was a composite of death or BPD assessed at 36 weeks' postmenstrual age. Twenty-nine secondary outcomes were analyzed up to hospital discharge, including death and BPD at 36 weeks' postmenstrual age., Results: Among 372 patients randomized (mean gestational age, 26 weeks; 55% male), 371 completed the trial; parents withdrew consent for 1 child treated with hydrocortisone. Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, -3.6% [95% CI, -12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54-1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks' postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, -8.2% [95% CI, -16.2% to -0.1%]; odds ratio, 0.59 [95% CI, 0.35-0.995]; P = .048). Twenty-one outcomes showed nonsignificant differences, including BPD (55.2% with hydrocortisone vs 50.0% with placebo; risk difference, 5.2% [95% CI, -4.9% to 15.2%]; odds ratio, 1.24 [95% CI, 0.82-1.86]; P = .31). Hyperglycemia requiring insulin therapy was the only adverse effect reported more often in the hydrocortisone group (18.2%) than in the placebo group (7.9%)., Conclusions and Relevance: Among mechanically ventilated very preterm infants, administration of hydrocortisone between 7 and 14 days after birth, compared with placebo, did not improve the composite outcome of death or BPD at 36 weeks' postmenstrual age. These findings do not support the use of hydrocortisone for this indication., Trial Registration: Netherlands National Trial Register Identifier: NTR2768.

Background: Vitamin A (VA) is crucial for lung growth and development. In premature infants, inadequate VA levels are associated with an increased risk of bronchopulmonary dysplasia (BPD). Intramuscular VA supplementation has been shown to decrease the incidence of BPD, but is not widely used in the clinical setting due to concerns about feasibility and pain. We studied VA kinetics, distribution, and the induction of early genetic expression of retinoid homeostatic genes in the lung after endotracheal and intravenous application in a preterm lamb model., Methods: Lambs were delivered prematurely after 85% of gestation, intubated, and ventilated for 3 hours. The animals were randomized to receive no VA ("control"), a bolus of VA intravenously ("i.v."), or VA endotracheally directly after administration of surfactant ("e.t.")., Results: Animals treated with VA endotracheally directly after administration of surfactant showed significant increases of VA in serum and lung compared to controls. Animals treated with a bolus of VA intravenously showed significant increases of VA in serum, lung, and liver; however, peak serum concentrations and mRNA levels of homeostatic genes raised concerns about toxicity in this group., Conclusions: Endotracheal VA supplementation in preterm lambs is feasible and might offer advantages in comparison to i.v. Further studies are warranted to explore biological effects in the context of BPD.

Bronchopulmonary dysplasia (BPD) is the most common complication after preterm birth. Pasteurized donor human milk (DHM) has increasingly become the standard of care for very preterm infants over the use of preterm formula (PF) if the mother's own milk (MOM) is unavailable. Studies have reported beneficial effects of DHM on BPD. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies on the effects of DHM on BPD and other respiratory outcomes. Eighteen studies met the inclusion criteria. Meta-analysis of RCTs could not demonstrate that supplementation of MOM with DHM reduced BPD when compared to PF (three studies, risk ratio (RR) 0.89, 95% confidence interval (CI) 0.60-1.32). However, meta-analysis of observational studies showed that DHM supplementation reduced BPD (8 studies, RR 0.78, 95% CI 0.67-0.90). An exclusive human milk diet reduced the risk of BPD, compared to a diet with PF and/or bovine milk-based fortifier (three studies, RR 0.80, 95% CI 0.68-0.95). Feeding raw MOM, compared to feeding pasteurized MOM, protected against BPD (two studies, RR 0.77, 95% CI 0.62-0.96). In conclusion, our data suggest that DHM protects against BPD in very preterm infants., Competing Interests: The authors declare no conflict of interest.

BackgroundThe aim of this study was to evaluate the potential of fecal volatile organic compounds (VOCs), obtained by means of an electronic nose device (Cyranose 320), as early non-invasive biomarker for BPD.MethodsIn this nested case-control study performed at three Neonatal Intensive Care Units, fecal samples obtained at postnatal age of 7, 14, 21, and 28 days from preterm infants with severe bronchopulmonary dysplasia (BPD) were compared with fecal VOC profiles from matched controls. Microbiota analysis was performed by means of IS-pro technique on fecal samples collected at 28 days postnatally.ResultsVOC profiles of infants developing severe BPD (n=15) could be discriminated from matched controls (n=15) at postnatal age of 14 days (area under the curve (±95% confidence interval), P-value, sensitivity, specificity; 0.72 (0.54-0.90), 0.040, 60.0%, 73.3%), 21 days (0.71 (0.52-0.90), 0.049, 66.7%, 73.3%) and 28 days (0.77 (0.59-0.96), 0.017, 69.2%, 69.2%) but not at 7 days. Intestinal microbiota did not differ between BPD subjects and controls.ConclusionFecal VOC profiles of infants developing BPD could be differentiated from controls at postnatal day 14, 21, and 28. VOC differences could not be directed to intestinal microbiota alterations but presumably reflect local and systemic metabolic and inflammatory pathways associated with BPD.

Preterm birth is the leading cause of death in newborns and children. Despite advances in perinatology, immature infants continue to face serious risks such chronic respiratory impairment from bronchopulmonary dysplasia (BPD). Current treatment options are insufficient and novel approaches are desperately needed. In recent years stem cells have emerged as potential candidates to treat BPD with mesenchymal stem/stromal cells (MSCs) being particularly promising. MSCs originate from several stem cell niches including bone marrow, skin, or adipose, umbilical cord, and placental tissues. Although the first MSCs clinical trials in BPD are ongoing, multiple questions remain open. In this review, we discuss the question of the optimal cell source (live cells or cell products), route and timing of the transplantation. Furthermore, we discuss MSCs possible capacities including migration, homing, pro-angiogenesis, anti-inflammatory, and tissue-regenerative potential as well., (Copyright © 2016. Published by Elsevier Ltd.)

Aim: Despite advances in perinatal management, there is a flat trend in incidences of respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in preterm infants. The main feature of BPD development in preterm infants is an imbalance between increased exposure to free radicals and inadequate antioxidant defences. We investigated the associations between BPD and lipid hydro-peroxide (LOOH) and glutathione (GSH) concentrations in bronchoalveolar lavage fluid (BALF)., Methods: In this prospective study, BALF samples were collected from 44 preterm infants with RDS and oxidative stress markers were measured in 11 with BPD and 33 controls without BPD., Results: LOOH levels were significantly higher (p < 0.01) in the BPD group (median 16.35; 25th-75th centile 13.75-17.05 nmol/mL) than in the no BPD group (median 13.18; 25th-75th centile 12.92-13.63 nmol/mL). Conversely, GSH levels were significantly lower in the BPD group (p < 0.01) (median 11.52; 25th-75th centile 6.95-13.85 μmol/mg) than the no BPD group (median: 18.69; 25th-75th centile: 13.89-23.64 μmol/mg). Multiple regression analysis showed significant correlations between BPD and mechanical ventilation time (p < 0.01) and LOOH levels (p < 0.05)., Conclusion: Early LOOH level increases in preterm infants developing BPD suggest that lung biochemical monitoring of sick infants might be possible and BPD could be predicted early by evaluating biomarkers., (©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Ureaplasma is an organism with low virulence and is a commensal of the lower genito-urinary tract in females. From here, it can gain entry in the amniotic fluid to cause inflammation in the amniotic compartment during pregnancy. Ureaplasma spp. are the most common organisms isolated from women with chorioamnionitis. Ureaplasma spp. are associated with increased risk for preterm labor and morbidity in the preterm neonate. However, there is some controversy regarding the importance of Ureaplasma in the pathogenesis of bronchopulmonary dysplasia (BPD). This article will review the microbiology of Ureaplasma, host innate immune responses, and the pathology of lung injury in animal models of Ureaplasma chorioamnionitis. We will review epidemiological studies of Ureaplasma and BPD in preterm infants and efficacy of antibiotics in preventing preterm labor and BPD., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Regenerative therapy based on stem cells is applied as standard therapy in pediatric oncology. Furthermore, they are frequently used to treat immunodeficiency disorders of infants. For severe neonatal diseases, e. g. hypoxic-ischemic encephalopathy in term neonates or bronchopulmonary dysplasia in preterm infants, animal models have been established. According to some first preclinical results stem cell administration appears as a promising tool to improve the clinical outcome in high-risk infants. Provided the benefit of regenerative therapies can further be evaluated in appropriate preclinical neonate models, carefully controlled clinical trials to assess the significance of regenerative therapies, such as autologous stem cell administration, are indicated., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Randomized controlled trials have shown that treatment of chronically ventilated preterm infants after the first week of life with dexamethasone reduces the incidence of the combined outcome death or bronchopulmonary dysplasia (BPD). However, there are concerns that dexamethasone may increase the risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. So far no randomized controlled trial has investigated its efficacy when administered after the first week of life to ventilated preterm infants., Methods/design: The SToP-BPD trial is a randomized double blind placebo controlled multicenter study including 400 very low birth weight infants (gestational age < 30 weeks and/or birth weight < 1250 grams), who are ventilator dependent at a postnatal age of 7 - 14 days. Hydrocortisone (cumulative dose 72.5 mg/kg) or placebo is administered during a 22 day tapering schedule. Primary outcome measure is the combined outcome mortality or BPD at 36 weeks postmenstrual age. Secondary outcomes are short term effects on the pulmonary condition, adverse effects during hospitalization, and long-term neurodevelopmental sequelae assessed at 2 years corrected gestational age. Analysis will be on an intention to treat basis., Discussion: This trial will determine the efficacy and safety of postnatal hydrocortisone administration at a moderately early postnatal onset compared to placebo for the reduction of the combined outcome mortality and BPD at 36 weeks postmenstrual age in ventilator dependent preterm infants.

Chronic lung damage (bronchopulmonary dysplasia (BPD)) is one of the most serious complications affecting preterm neonates. During the last decade the aetiology of BPD has changed. Whereas 'classic BPD' was characterised mainly by lung damage and fibrosis caused by oxygen toxicity and mechanical ventilation, 'new BPD' is characterised by a disorder in lung development. This aetiological shift has been brought about by improved survival in extremely premature infants as a result of, for instance, antenatal corticosteroid administration and postnatal surfactant therapy. New BPD requires a new therapeutic approach. Therapeutic options for developing BPD include caffeine, vitamin A and postnatal corticosteroids. Once BPD has occurred, diuretics and inhaled bronchodilators and corticosteroids may be useful. However, the available therapies decrease the risk of developing BPD by just a small percent. In the future, artificial surfactants and non-invasive ventilation may prove to be useful in the prevention of BPD.

A systemic inflammatory response of the fetus, reflected by histologic funisitis, is a risk factor for bronchopulmonary dysplasia (BPD). Impaired pulmonary angiogenesis accompanied by simplification and rarification of alveoli is a histologic hallmark of BPD. Angiopoietin-1 mediates vascular development, maturation, and stabilization. Endostatin mainly acts as an angiostatic factor. We hypothesized that funisitis was associated with changes of endostatin and angiopoietin-1 concentrations in the airways and that an imbalance between the factors might be associated with BPD or death. We measured concentrations of angiopoietin-1 and endostatin by enzyme-linked immunosorbent assay in tracheobronchial aspirate fluid samples of 42 ventilated preterm infants during postnatal days 1 through 15. The secretory component for IgA served as reference protein. A standardized histologic examination was used to distinguish three groups: chorioamnionitis, funisitis, and controls without inflammation. Concentrations of the mediators steadily decreased. Funisitis was associated with lower concentrations of both proteins, which might impair their physiologic activities in pulmonary angiogenesis. An increase of the ratio angiopoietin-1/endostatin until day 7 of life indicated a shift of the mediators potentially favoring angiogenesis. However, infants, who developed BPD or died, had a decreased ratio on days 1, 3, and 15, suggesting an imbalance toward inhibition of pulmonary angiogenesis.

Objective: Macrophage migration inhibitory factor is a proinflammatory mediator of innate immunity, enhances cell growth, and plays a role in preterm delivery. We speculated that funisitis, reflecting fetal systemic inflammation, would be associated with higher concentrations of macrophage migration inhibitory factor in airways of extremely premature infants., Study Design: We measured macrophage migration inhibitory factor by enzyme linked immunosorbent assay in tracheobronchial aspirate fluid of 35 ventilated infants less than 30 weeks' gestational age, throughout the first week of life. Three groups were distinguished histologically: chorioamnionitis, funisitis, and control., Results: Unexpectedly, funisitis was associated with significantly decreased macrophage migration inhibitory factor in tracheobronchial aspirate fluid on day 1 (P < .01) and levels remained lower than in the chorioamnionitis group thereafter. For the 35 patients in total, macrophage migration inhibitory factor steadily declined., Conclusion: Decreased macrophage migration inhibitory factor concentrations in airways of extremely premature infants with systemic fetal inflammation early in life might predispose them to pulmonary infection and interfere with maturation of the lung, contributing to adverse pulmonary outcome.

Intratracheal endotoxin causes acute inflammation in the adult lung, and injurious styles of mechanical ventilation can result in systemic inflammation derived from the lungs. We asked how ventilated premature and near-term lungs responded to intratracheal endotoxin and if systemic inflammation occurred. Lambs delivered at 130 d gestational age (GA) were treated with surfactant or surfactant plus endotoxin (0.1 mg/kg or 10 mg/kg) (Escherichia coli, serotype O55:B5) and were ventilated for 6 h. Both endotoxin doses resulted in impaired gas exchange and systemic inflammation in the preterm lambs. Lambs at 141 d GA (term 146 d) were given either 10 mg/kg intratracheal endotoxin, 10 mg/kg endotoxin plus high tidal volume ventilation for the first 30 min of life, or 5 microg/kg endotoxin given intravenously. Endotoxin alone (10 mg/kg) caused lung inflammation but no systemic effects after 6 h of ventilation. Lambs given 10 mg/kg endotoxin plus high tidal volume ventilation or 5 microg/kg endotoxin intravenously had decreased gas exchange and systemic inflammation. Endotoxin was detected in the plasma of lambs at 130 d GA but not at 141 d GA. Inflammation in the lungs was more severe in preterm animals. Mechanical ventilation of the endotoxin-exposed preterm lung resulted in systemic effects at a low endotoxin dose and without high tidal volume ventilation.

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.