Maria-Jantje Brinkhaus

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.

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.