Christiane E.L. Dammann

Bronchopulmonary dysplasia and inflammatory biomarkers in the premature neonate

Bronchopulmonary dysplasia (BPD) is the most common, serious sequela of premature birth. Inflammation is a major contributor to the pathogenesis of BPD. Often initiated by a pulmonary fetal inflammatory response, lung inflammation is exacerbated by mechanical ventilation and exposure to supplemental oxygen. In response to these initiators of injury, a complex interaction occurs between proteins that attract inflammatory cells (ie, chemokines), proteins that facilitate the transendothelial migration of inflammatory cells from blood vessels (ie, adhesion molecules), proteins that promote tissue damage (ie, pro-inflammatory cytokines and proteases), and proteins that modulate the process (eg, anti-inflammatory cytokines, binding proteins and receptor antagonists). In addition, during recovery from inflammatory injury, growth factors and other substances that control normal lung growth and mediate repair influence subsequent lung structure. In this review, we discuss the role of each aspect of the inflammatory process in the development of BPD. This discussion will include data from measurements of biomarkers in samples of fluid aspirated from the airways of human infants relevant to each phase of inflammation. Despite their limitations, these measurements provide some insight into the role of inflammation in the development of BPD and may be useful in identifying infants at risk for the disease.

High or low oxygen saturation and severe retinopathy of prematurity: a meta-analysis

CONTEXT: Low oxygen saturation appears to decrease the risk of severe retinopathy of prematurity (ROP) in preterm newborns when administered during the first few weeks after birth. High oxygen saturation seems to reduce the risk at later postmenstrual ages (PMAs). However, previous clinical studies are not conclusive individually. OBJECTIVE: To perform a systematic review and meta-analysis to report the association between severe ROP incidence of premature infants with high or low target oxygen saturation measured by pulse oximetry. METHODS: Studies were identified through PubMed and Embase literature searches through May 2009 by using the terms “retinopathy of prematurity and oxygen” or “retinopathy of prematurity and oxygen therapy.” We selected 10 publications addressing the association between severe ROP and target oxygen saturation measured by pulse oximetry. Using a random-effects model we calculated the summary-effect estimate. We visually inspected funnel plots to examine possible publication bias. RESULTS: Low oxygen saturation (70%–96%) in the first several postnatal weeks was associated with a reduced risk of severe ROP (risk ratio [RR]: 0.48 [95% confidence interval (CI): 0.31–0.75]). High oxygen saturation (94%–99%) at ≥32 weeks’ PMA was associated with a decreased risk for progression to severe ROP (RR: 0.54 [95% CI: 0.35–0.82]). CONCLUSIONS: Among preterm infants with a gestational age of ≤32 weeks, early low and late high oxygen saturation were associated with a reduced risk for severe ROP. We feel that a large randomized clinical trial with long-term developmental follow-up is warranted to confirm this meta-analytic result.

Lung and brain damage in preterm newborns, and their association with gestational age, prematurity subgroup, infection/inflammation and long term outcome

Compared with those born at term, preterm newborns are at an increased risk of short term disorders of the lung (bronchopulmonary dysplasia; BPD) and the brain (white matter damage; WMD), and of long term developmental and pulmonary dysfunctions. Although all of these adverse outcomes are associated with low gestational age, brain, but not lung, damage appears to be associated with the prematurity subgroup [spontaneous preterm labour and/or preterm prelabour rupture of membranes (PPROM) vs pregnancy‐induced hypertension (PIH)]. Part of the association between brain damage and prematurity subgroup might be due to a differential exposure of members of these subgroups to perinatal infection/inflammation. There is a lack of studies evaluating the association of antenatal and perinatal risk factors with late childhood pulmonary dysfunction among those born during the second trimester. In this paper we discuss the complexities that paediatricians, perinatologists and perinatal epidemiologists face as they try to understand the contributions of factors associated with preterm birth to neonatal and childhood disorders.

Immaturity, perinatal inflammation, and retinopathy of prematurity: A multi-hit hypothesis

OBJECTIVE To explore the relationship among markers of infection/inflammation in their association with retinopathy of prematurity (ROP). METHODS We studied clinical characteristics and 4 single nucleotide polymorphisms in infection/inflammation-associated genes in a group of 73 children with a gestational age<32 weeks. Forty-four children (60%) had ROP, of whom 13 (30% of those with ROP) progressed to stage 3 ROP. No child had grade 4 or 5 ROP. We employed both descriptive and analytic statistical methods. RESULTS Clinical variables of infection/inflammation were consistently associated with an increased risk of ROP. Among infants with ROP, they were also associated with progression to ROP grade 3. Genetic markers were not associated with ROP occurrence, but with progression to high grade disease. In tri-variable analyses exploring the effects of gestational age <29 weeks, clinical chorioamnionitis (CAM) and neonatal systemic inflammatory response syndrome (SIRS) on ROP occurrence, low gestational age was the most important antecedent, while additional individual or joint exposure to SIRS and CAM add appreciably to this risk of progression to high grade disease. CONCLUSION Both antenatal and neonatal exposure to inflammation appear to contribute to the increased ROP risk in preterm infants.

Lung and Brain Damage in Preterm Newborns Are They Related? How? Why?

The relationships among bronchopulmonary dysplasia (BPD), brain white matter damage (WMD) and cerebral palsy (CP) are far from simple. Apparently, BPD and WMD are not associated, while BPD and CP are. The most likely explanation for this paradox is that ultrasound imaging does not identify all the WMD that might lead to CP (‘tip-of-the-iceberg effect’). We discuss further methodological inconsistencies, etiological peculiarities related to antenatal infection/inflammation, and intervention-related issues. In particular, we expand on the multiple-hit scenario in the etiology of BPD and offer support for the hypothesis that it is not lung disease, but factors associated with lung disease (e.g. postnatal steroid exposure) that increase the risk for developmental disability in childhood.

Infection, Oxygen, and Immaturity: Interacting Risk Factors for Retinopathy of Prematurity

Background: Interactions among known risk factors for retinopathy of prematurity (ROP) remain to be clarified. Objectives: The aim of this study was to identify risk factors associated with ROP and to explore the interrelationships between prominent risk factors for ROP. Methods: From an institutional cohort of 1,646 very preterm newborns with gestational age <30 weeks or birth weight <1,501 g, we selected infants with a gestational age <30 weeks who met the criteria for ROP screening (n = 622) for a nested case-control analysis. Results: Of the 622 eligible newborns, 293 (47%) were diagnosed with ROP. From multivariable analyses, gestational age <26 weeks (OR 2.9, CI 1.7–4.9), oxygen exposure at 28 days (OR 1.7, CI 1.0–2.7), and neonatal sepsis (OR 2.1, CI 1.4–3.2) emerged as prominent risk factors for ROP. Oxygen- associated ROP risk was more prominent among infants of 23–25 weeks’ gestational age, while infection-associated ROP risk was higher among infants born at 28–29 weeks. The OR for the joint effect of all 3 risk factors (23.5) was higher than would have been expected under the additive (8.6) and the multiplicative (16.5) patterns of interaction. Conclusions: Our study suggests that neonatal sepsis, oxygen exposure, and low gestational age are not only independently associated with a significantly increased risk of ROP, but also interact beyond additive and even multiplicative patterns.

Pulmonary function at school-age in surfactant-treated preterm infants

A follow‐up study was conducted in 40 children who had been enrolled in a prospective randomized study of exogenous surfactant therapy for respiratory distress syndrome (RDS) (n = 22; S) or placebo (n = 18; P) to determine long‐term pulmonary sequelae of surfactant treatment in premature infants with RDS. At follow‐up, mean (SD) age was 6.63 (0.18) and 6.55 (0.23) years for S and P, respectively. Complete lung function tests (LFT) were attempted in all patients.

Stretch-induced Fetal Type II Cell Differentiation Is Mediated via ErbB1-ErbB4 Interactions

Background: Mechanical forces and ErbB receptors are critical for fetal lung development. Results: Deletion of ErbB1 or down-regulation or ErbB4 prevented stretch-induced type II cell differentiation via ERK. Conclusion: Interactions between ErbB1 and ErbB4 are critical for stretch-induced type II cell differentiation. Significance: Learning how mechanical signal regulate fetal lung development is critical to develop strategies to accelerate lung maturation. Stretch-induced differentiation of lung fetal type II epithelial cells is mediated through EGFR (ErbB1) via release of HB-EGF and TGF-α ligands. Employing an EGFR knock-out mice model, we further investigated the role of the ErbB family of receptors in mechanotranduction during lung development. Deletion of EGFR prevented endogenous and mechanical stretch-induced type II cell differentiation via the ERK pathway, which was rescued by overexpression of a constitutively active MEK. Interestingly, the expression of ErbB4, the only ErbB receptor that EGFR co-precipitates in wild-type cells, was decreased in EGFR-deficient type II cells. Similar to EGFR, ErbB4 was activated by stretch and participated in ERK phosphorylation and type II cell differentiation. However, neuregulin (NRG) or stretch-induced ErbB4 activation were blunted in EGFR-deficient cells and not rescued after ErbB4 overexpression, suggesting that induction of ErbB4 phosphorylation is EGFR-dependent. Finally, we addressed how shedding of ligands is regulated by EGFR. In knock-out cells, TGF-α, a ligand for EGFR, was not released by stretch, while HB-EGF, a ligand for EGFR and ErbB4, was shed by stretch although to a lower magnitude than in normal cells. Release of these ligands was inhibited by blocking EGFR and ERK pathway. In conclusion, our studies show that EGFR and ErbB4 regulate stretch-induced type II cell differentiation via ERK pathway. Interactions between these two receptors are important for mechanical signals in lung fetal type II cells. These studies provide novel insights into the cell signaling mechanisms regulating ErbB family receptors in lung cell differentiation.

ErbB4 deletion leads to changes in lung function and structure similar to bronchopulmonary dysplasia

Neuregulin is an important growth factor in fetal surfactant synthesis, and downregulation of its receptor, ErbB4, impairs fetal surfactant synthesis. We hypothesized that pulmonary ErbB4 deletion will affect the developing lung leading to an abnormal postnatal lung function. ErbB4-deleted lungs of 11- to 14-wk-old adult HER4heart mice, rescued from their lethal cardiac defects, were studied for the effect on lung function, alveolarization, and the surfactant system. ErbB4 deletion impairs lung function and structure in HER4heart mice resulting in a hyperreactive airway system and alveolar simplification, as seen in preterm infants with bronchopulmonary dysplasia. It also leads to a downregulation of surfactant protein D expression and an underlying chronic inflammation in these lungs. Our findings suggest that this animal model could be used to further study the pathogenesis of bronchopulmonary dysplasia and might help design protective interventions.

ErbB4 regulates the timely progression of late fetal lung development.

The ErbB4 receptor has an important function in fetal lung maturation. Deletion of ErbB4 leads to alveolar hypoplasia and hyperreactive airways similar to the changes in bronchopulmonary dysplasia (BPD). BPD is a chronic pulmonary disorder affecting premature infants as a consequence of lung immaturity, lung damage, and abnormal repair. We hypothesized that proper ErbB4 function is needed for the timely progression of fetal lung development. An ErbB4 transgenic cardiac rescue mouse model was used to study the effect of ErbB4 deletion on fetal lung structure, surfactant protein (SP) expression, and synthesis, and inflammation. Morphometric analyses revealed a delayed structural development with a significant decrease in saccular size at E18 and more pronounced changes at E17, keeping these lungs in the canalicular stage. SP-B mRNA expression was significantly down regulated at E17 with a subsequent decrease in SP-B protein expression at E18. SP-D protein expression was significantly decreased at E18. Surfactant phospholipid synthesis was significantly decreased on both days, and secretion was down regulated at E18. We conclude that pulmonary ErbB4 deletion results in a structural and functional delay in fetal lung development, indicating a crucial regulatory role of ErbB4 in the timely progression of fetal lung development.