Physiopathologie des anomalies du développement alvéolaire dans le RCIU (approche expérimentale et clinique)

Une croissance intra-utérine insuffisante représente, avec la prématurité et les malfor-mations congénitales, une des principales causes de morbidité et de mortalité néonatales. Ces pathologies sont liées entre elles, les nouveau-nés prématurés étant souvent atteints de RCIU (RCIU). Les études épidémiologiques récentes ont montré que le RCIU était associé à une augmentation de la morbidité respiratoire dès la période néonatale, avec, en particulier, une augmentation du risque de dysplasie broncho-pulmonaire (DBP), principale séquelle respira-toire de la prématurité. La DBP est caractérisée par des anomalies du développement alvéo-laire et vasculaire, considérées comme les conséquences d agressions multiples sur un poumon immature. La physiopathologie exacte reste encore largement méconnue. Nous nous sommes intéressés dans ce travail au lien entre RCIU et DBP avec un abord expérimental et clinique. Alors que les études épidémiologiques sont relativement concordantes sur le lien entre RCIU et DBP, les études expérimentales, montrent des résultats divers tant sur le développement pulmonaire qu au niveau moléculaire. Nous avons donc voulu identifier, dans un premier temps, un modèle de RCIU reproduisant les anomalies du développement alvéolaire observées chez l Homme en utilisant trois modèles précédemment validés chez le rat : un modèle de res-triction protidique per-gestationnelle , un modèle de ligature unilatérale de l artère utérine, un modèle d injection d un inhibiteur chimique de la NO synthase, le L NAME. Seule la restric-tion protidique anténatale permet de reproduire à long terme des lésions de l alvéolisation proches de celles observées dans la DBP. En revanche, dans ce modèle, les modifications des principaux gènes identifiés précédemment dans les anomalies le développement alvéolaire ne sont pas observées, que ce soit avant, pendant ou après l alvéolisation. Ce résultat nous a ame-né à entreprendre une étude multigénique qui a permis d identifier plusieurs voies modifiées pendant l alvéolisation dans ce modèle. Parmi celles-ci, les gènes impliqués dans la contractili-té et l adhésion cellulaire, l immunité ou la voie des Peroxisome Proliferator-Activated Re-ceptor . Dans la partie clinique de cette étude, nous avons évalué le risque de DBP chez les extrêmes prématurés atteints de RCIU dont les mères présentaient des signes de pathologie vasculaire de la grossesse (prééclampsie). Cette étude rétrospective unicentrique sur 184 en-fants a permis de comparer des enfants atteints de RCIU à des enfants eutrophes pris en charge de manière homogène. Le RCIU d origine vasculaire multiplie le risque de DBP par 6. Un marqueur précoce de l évolution vers une DBP est un taux de plaquettes bas à la naissance, évoquant le rôle d un taux élevé de facteurs anti-angiogéniques circulants. Une étude est en cours pour corréler les facteurs anti-angiogéniques circulants présents chez les mères pré-éclamptiques au devenir respiratoire, en particulier à l évolution vers une DBP, de leurs nou-veau-nés d âge gestationnel inférieur à 30 semaines d aménorrhée. En conclusion, nous avons montré expérimentalement que seule la restriction protidique anténatale chez le rat reproduisait les troubles de l alvéolisation comparables à ceux observés dans la DBP. De nouvelles voies moléculaires potentiellement impliquées dans les anomalies de l alvéolisation ont été mises en évidence. Par ailleurs, le rôle de facteurs anti-angiogéniques d origine maternelle comme fac-teurs de développement d une DBP est en cours d évaluation.Insufficient intrauterine growth is with prematurity and congenital malformations, a major cause of neonatal morbidity and mortality. These conditions are interrelated, the preterm infants often suffered of intrauterine growth restriction (IUGR). Recent epidemiological stud-ies showed that IUGR was associated with increased respiratory morbidity as soon as the ne-onatal period, with an increased risk of bronchopulmonary dysplasia (BPD), the main respira-tory sequelae of prematurity. BPD is characterized by impaired alveolar and vascular devel-opment and is the consequence of multiple insults on an immature lung. The exact pathophysi-ology is still largely unknown. We study in this work the relationship between IUGR and DBP with an experimental and clinical approach. While epidemiological studies are relatively concordant on the relationship between IUGR and BPD, experimental studies showed various results in lung development and molecular process. We wanted to identify, at first, a model of IUGR reproducing impaired alveolar development observed in humans using three previously validated models in rats: a model of per-gestational protein restriction, a model of unilateral ligation uterine artery, an injection pattern of a chemical inhibitor of NO synthase, L NAME. Only antenatal protein restriction can reproduce long-term impaired alveolarization as those observed in BPD. However, in this model, changes in key genes previously identified in pathological alveolar development are not observed before, during or after alveolarization. This result led us to perform a genome-wide analysis which identified several modified path-ways during alveolarization. Among these, the genes involved in the cardiac contractility , cell adhesion molecules , immunity , molecular adhesion or the "Peroxisome Proliferator-Activated Receptor" pathways. In the clinical part of this study, we evaluated the risk of BPD in extreme preterm infants with IUGR whose mothers had evidence of vascular disease of pregnancy (preeclampsia). This single-center retrospective study of 184 children was used to compare children with IUGR in adjusted for gestational age children. The vascular IUGR increases the risk of DBP by 6. An early marker of progression to BPD is a low platelet count at birth, referring to the role of high levels of circulating anti-angiogenic factors. A study is ongoing to correlate circulating anti-angiogenic factors present in preeclamptic mothers to res-piratory outcome and particularly BDP, in newborn younger than 30 weeks of gestational age at birth. In conclusion, we have shown experimentally that only prenatal protein restriction in rats reproduced impaired alveolarization comparable to those observed in the BPD. New mo-lecular pathways potentially involved in the impaired alveolarization were highlighted. More-over, the role of placental anti-angiogenic factors leading to development of BPD is evaluat-ed.PARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Matrix Metalloproteinase Gene Polymorphisms and Bronchopulmonary Dysplasia: Identification of MMP16 as a New Player in Lung Development

International audienceBACKGOUND: Alveolarization requires coordinated extracellular matrix remodeling, a process in which matrix metalloproteinases (MMPs) play an important role. We postulated that polymorphisms in MMP genes might affect MMP function in preterm lungs and thus influence the risk of bronchopulmonary dysplasia (BPD). METHODS AND FINDINGS: Two hundred and eighty-four consecutive neonates with a gestational age of <28 weeks were included in this prospective study. Forty-five neonates developed BPD. Nine single-nucleotide polymorphisms (SNPs) were sought in the MMP2, MMP14 and MMP16 genes. After adjustment for birth weight and ethnic origin, the TT genotype of MMP16 C/T (rs2664352) and the GG genotype of MMP16 A/G (rs2664349) were found to protect from BPD. These genotypes were also associated with a smaller active fraction of MMP2 and with a 3-fold-lower MMP16 protein level in tracheal aspirates collected within 3 days after birth. Further evaluation of MMP16 expression during the course of normal human and rat lung development showed relatively low expression during the canalicular and saccular stages and a clear increase in both mRNA and protein levels during the alveolar stage. In two newborn rat models of arrested alveolarization the lung MMP16 mRNA level was less than 50% of normal. CONCLUSIONS: MMP16 may be involved in the development of lung alveoli. MMP16 polymorphisms appear to influence not only the pulmonary expression and function of MMP16 but also the risk of BPD in premature infants

Systemic Steroids in Preventing Bronchopulmonary Dysplasia (BPD): Neurodevelopmental Outcome According to the Risk of BPD in the EPICE Cohort

Background: Postnatal steroids (PNS) have been used to prevent bronchopulmonary dysplasia (BPD) in preterm infants but have potential adverse effects on neurodevelopment. These effects might be modulated by their risk of BPD. We aimed to compare patients’ neurodevelopment with PNS treatment according to their risk of BPD in a European cohort. Methods: We developed a prediction model for BPD to classify infants born between 24 + 0 and 29 + 6 weeks of gestation in three groups and compared patients’ neurological outcome at two years of corrected age using the propensity score (PS) method. Results: Of 3662 neonates included in the analysis, 901 (24.6%) were diagnosed with BPD. Our prediction model for BPD had an area under the ROC curve of 0.82. In the group with the highest risk of developing BPD, PNS were associated with an increased risk of gross motor impairment: OR of 1.95 after IPTW adjustment (95% CI 1.18 to 3.24, p = 0.010). This difference existed regardless of the type of steroid used. However, there was an increased risk of cognitive anomalies for patients treated with dexa/betamethasone that was no longer observed with hydrocortisone. Conclusions: This study suggests that PNS might be associated with an increased risk of gross motor impairment regardless of the group risk for BPD. Further randomised controlled trials exploring the use of PNS to prevent BPD should include a risk-based evaluation of neurodevelopmental outcomes. This observation still needs to be confirmed in a randomised controlled trial

Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia

Peer reviewe

Recommendations for mechanical ventilation of critically ill children from the Paediatric Mechanical Ventilation Consensus Conference (PEMVECC)

Purpose: Much of the common practice in paediatric mechanical ventilation is based on personal experiences and what paediatric critical care practitioners have adopted from adult and neonatal experience. This presents a barrier to planning and interpretation of clinical trials on the use of specific and targeted interventions. We aim to establish a European consensus guideline on mechanical ventilation of critically children. Methods: The European Society for Paediatric and Neonatal Intensive Care initiated a consensus conference of international European experts in paediatric mechanical ventilation to provide recommendations using the Research and Development/University of California, Los Angeles, appropriateness method. An electronic literature search in PubMed and EMBASE was performed using a combination of medical subject heading terms and text words related to mechanical ventilation and disease-specific terms. Results: The Paediatric Mechanical Ventilation Consensus Conference (PEMVECC) consisted of a panel of 15 experts who developed and voted on 152 recommendations related to the following topics: (1) general recommendations, (2) monitoring, (3) targets of oxygenation and ventilation, (4) supportive measures, (5) weaning and extubation readiness, (6) normal lungs, (7) obstructive diseases, (8) restrictive diseases, (9) mixed diseases, (10) chronically ventilated patients, (11) cardiac patients and (12) lung hypoplasia syndromes. There were 142 (93.4%) recommendations with "strong agreement". The final iteration of the recommendations had none with equipoise or disagreement. Conclusions: These recommendations should help to harmonise the approach to paediatric mechanical ventilation and can be proposed as a standard-of-care applicable in daily clinical practice and clinical research

Early inhaled budesonide for the prevention of bronchopulmonary dysplasia

BACKGROUND Systemic glucocorticoids reduce the incidence of bronchopulmonary dysplasia among extremely preterm infants, but they may compromise brain development. The effects of inhaled glucocorticoids on outcomes in these infants are unclear. METHODS We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to early (within 24 hours after birth) inhaled budesonide or placebo until they no longer required oxygen and positive-pressure support or until they reached a postmenstrual age of 32 weeks 0 days. The primary outcome was death or bronchopulmonary dysplasia, confirmed by means of standardized oxygen-saturation monitoring, at a postmenstrual age of 36 weeks. RESULTS A total of 175 of 437 infants assigned to budesonide for whom adequate data were available (40.0%), as compared with 194 of 419 infants assigned to placebo for whom adequate data were available (46.3%), died or had bronchopulmonary dysplasia (relative risk, stratified according to gestational age, 0.86; 95% confidence interval [CI], 0.75 to 1.00; P = 0.05). The incidence of bronchopulmonary dysplasia was 27.8% in the budesonide group versus 38.0% in the placebo group (relative risk, stratified according to gestational age, 0.74; 95% CI, 0.60 to 0.91; P = 0.004); death occurred in 16.9% and 13.6% of the patients, respectively (relative risk, stratified according to gestational age, 1.24; 95% CI, 0.91 to 1.69; P = 0.17). The proportion of infants who required surgical closure of a patent ductus arteriosus was lower in the budesonide group than in the placebo group (relative risk, stratified according to gestational age, 0.55; 95% CI, 0.36 to 0.83; P = 0.004), as was the proportion of infants who required reintubation (relative risk, stratified according to gestational age, 0.58; 95% CI, 0.35 to 0.96; P = 0.03). Rates of other neonatal illnesses and adverse events were similar in the two groups. CONCLUSIONS Among extremely preterm infants, the incidence of bronchopulmonary dysplasia was lower among those who received early inhaled budesonide than among those who received placebo, but the advantage may have been gained at the expense of increased mortality

Effects of Phosphodiesterase 4 Inhibition on Alveolarization and Hyperoxia Toxicity in Newborn Rats

International audienceBACKGROUND: Prolonged neonatal exposure to hyperoxia is associated with high mortality, leukocyte influx in airspaces, and impaired alveolarization. Inhibitors of type 4 phosphodiesterases are potent anti-inflammatory drugs now proposed for lung disorders. The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury. METHODOLOGY/FINDINGS: Rat pups were placed under hyperoxia (FiO2>95%) or room air from birth, and received rolipram or its diluent daily until sacrifice. Mortality rate, weight gain and parameters of lung morphometry were recorded on day 10. Differential cell count and cytokine levels in bronchoalveolar lavage and cytokine mRNA levels in whole lung were recorded on day 6. Rolipram diminished weight gain either under air or hyperoxia. Hyperoxia induced huge mortality rate reaching 70% at day 10, which was prevented by rolipram. Leukocyte influx in bronchoalveolar lavage under hyperoxia was significantly diminished by rolipram. Hyperoxia increased transcript and protein levels of IL-6, MCP1, and osteopontin; rolipram inhibited the increase of these proteins. Alveolarization was impaired by hyperoxia and was not restored by rolipram. Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count. CONCLUSIONS: Although inhibition of phosphodiesterases 4 prevented mortality and lung inflammation induced by hyperoxia, it had no effect on alveolarization impairment, which might be accounted for by the aggressiveness of the model. The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization