ABSTRACT
Pulmonary ErbB4 deletion leads to a delay in fetal lung development, alveolar simplification, and lung function disturbances in adult mice. We generated a model of intrauterine infection in ErbB4 transgenic mice to study the additive effects of antenatal LPS administration and ErbB4 deletion during fetal lung development. Pregnant mice were treated intra-amniotically with an LPS dose of 4 µg at E17 of gestation. Lungs were analyzed 24 h later. A significant influx of inflammatory cells was seen in all LPS-treated lungs. In heterozygote control lungs, LPS treatment resulted in a delay of lung morphogenesis characterized by a significant increase in the fraction of mesenchyme, a decrease in gas exchange area, and disorganization of elastic fibers. Surfactant protein (Sftp)b and Sftpc were upregulated, but mRNA of Sftpb and Sftpc was downregulated compared with non-LPS-treated controls. The mRNA of Sftpa1 and Sftpd was upregulated. In ErbB4-deleted lungs, the LPS effects were more pronounced, resulting in a further delay in morphological development, a more pronounced inflammation in the parenchyma, and a significant higher increase in all Sftp. The effect on Sftpb and Sftpc mRNA was somewhat different, resulting in a significant increase. These results imply a major role of ErbB4 in LPS-induced signaling in structural and functional lung development.
Subject(s)
Alveolar Epithelial Cells/metabolism , ErbB Receptors/deficiency , Fetus/metabolism , Inflammation/metabolism , Lipopolysaccharides/pharmacology , Lung/metabolism , Protein Isoforms/metabolism , Signal Transduction/genetics , Alveolar Epithelial Cells/cytology , Alveolar Epithelial Cells/drug effects , Animals , Cell Movement/drug effects , Elastic Tissue , ErbB Receptors/genetics , Female , Fetus/drug effects , Fetus/embryology , Gene Expression Regulation, Developmental/drug effects , Inflammation/embryology , Inflammation/genetics , Intercellular Signaling Peptides and Proteins , Lipopolysaccharides/adverse effects , Lung/cytology , Lung/drug effects , Lung/embryology , Mice , Mice, Knockout , Peptides/genetics , Peptides/metabolism , Pregnancy , Protein Isoforms/genetics , Pulmonary Surfactant-Associated Protein C , RNA, Messenger/analysis , RNA, Messenger/biosynthesis , Receptor, ErbB-4 , Signal Transduction/drug effects , UterusABSTRACT
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.
Subject(s)
ErbB Receptors/metabolism , Fetus/physiology , Animals , Bronchopulmonary Dysplasia/metabolism , CD11b Antigen/metabolism , Cells, Cultured , ErbB Receptors/genetics , Female , Fetus/anatomy & histology , Fibroblasts/cytology , Fibroblasts/physiology , Heart/embryology , Heart/physiology , Humans , Infant, Newborn , Mice , Mice, Transgenic , Pregnancy , Pulmonary Surfactants/chemistry , Pulmonary Surfactants/metabolism , Receptor, ErbB-4ABSTRACT
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.