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ErbB4 Deletion Leads to Changes in Lung Function and Structure Similar to Bronchopulmonary Dysplasia
ABSTRACT
Neuregulin is an important growth factor in fetal surfactant synthesis and down regulation 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 to14 weeks 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 down regulation 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
[Publication Page: A90] ATS 2007 • San Francisco International Conference
Pulmonary Hypoplasia and Defective Surfactant System in ErbB4-Deleted Fetal Mice
ABSTRACT
ErbB4 is expressed in late fetal lung cells and functions as a common dimerization partner for other ErbB receptors. Downregulation of ErbB4 by siRNA inhibits surfactant synthesis. It is unknown how pulmonary ErbB4 knock-out affects fetal lung development. HER4heart-/- transgenic mice, rescued from their lethal cardiac defect, provide a valuable tool to study the function of ErbB4 during fetal lung development. We hypothesized that the deletion of ErbB4 will affect fetal lung development. We studied this hypothesis by analyzing lung morphology and surfactant synthesis and secretion in fetal ErbB4-deleted lungs. E18 HER4heart-/- lungs were significantly decreased in the thickness of the saccular septa and increased in the surface density of saccules. E17 lungs showed a delayed development of pulmonary saccules. Surfactant lipid synthesis and secretion were both reduced in E18 and E17, but were not affected in E16 HER4heart-/- lungs. Expression of surfactant proteins was affected in E18 HER4heart-/- lungs, but no significant differences in surfactant protein expression were found in E17 lungs.
In vivo deletion of ErbB4 receptor in the fetal lung impairs surfactant synthesis and secretion, as well as late fetal development, indicating a crucial role for ErbB4 in fetal lung development.
[Publication Page: A88] ATS 2007 • San Francisco International Conference
Lipopolysaccharide Treatment Potentiates the Structural Delay of Lung Development in ErbB4-Deleted Fetal Lungs
ABSTRACT
ErbB4 plays an important role in the developing lung. Deletion of ErbB4 delays structural development and the onset of fetal surfactant synthesis. Adult animals develop a hyper reactive airway system and alveolar simplification, similar to preterm infants with bronchopulmonary dysplasia. Antenatal lipopolysaccharide (LPS) exposure also interrupts structural development.
The objective of the study is to study the additive effects of antenatal LPS administration and ErbB4 deletion on structural lung development and the resulting ErbB receptor regulation.
Pregnant HER4heart mice were treated with LPS (100 g/kg, intra-peritoneal) at d17 of gestation. Lungs were isolated 24 hour later for stereological and ErbB receptor analyses.
LPS exposure resulted in delay of structural development leading to an increased volume density of lung mesenchyme and decreased volume density of ductal airspace. LPS-treated lungs were at the canalicular stage and saline-treated control lungs were at the saccular stage. ErbB4-deleted lungs treated with LPS showed an even further delay in structural lung development with the volume density of lung mesenchyme being increased by 70% and the volume density of ductal airspace decreased by 13% when compared to the ErbB4-deleted control lungs. Western blotting showed decreased phosphorylation, but increased ErbB2 protein expression in LPS-treated lungs.
ErbB4 deletion potentiates the LPS-induced delay in structural development implying a role of ErbB4 in response to inflammatory lung injury. ErbB2 is up-regulated in inflammation, implying a role in the signaling of this injury. It might be speculated that ErbB4 has a more protective and ErbB2 a more injury promoting role in inflammation.
ATS 2008 • Toronto International
Conference Filename: 952117
Abstract Category: 03.03 - PED - Developmental Lung Biology
ErbB4 Regulates the Intracellular Distribution of Surfactant Proteins in Alveolar Epithelial Type II Cells
ABSTRACT
Alveolar epithelial type II cells (AE II) synthesize, store, and recycle surfactant. Lamellar bodies (lb) are the storage organelles of hydrophobic surfactant proteins (SP) and multivesicular bodies (mvb) of hydrophilic (SP-A and SP-D) and also the precursors of hydrophobic SP. ErbB4 is an important regulator of lung development and its deletion leads to an alveolar simplification, abnormal lung function, SP-D downregulation, and signs of chronical inflammation.
The objective of the study is to evaluate the effects of ErbB4 deletion on intracellular localization of SP and the structure of lb.
Volume fraction and size of lb was determined stereologically in sections of ErbB4 deleted transgenic adult lungs (HER4heart). Intracellular SP was detected by quantitative immunoelectron microscopy and the relative labeling index (RLI).
Results: ErbB4 deletion had no significant effect on size of AE II and volume fractions of subcellular organelles. SP-C was predominantly distributed in lb and mvb independent of the genotype. SP-A was preferentially localized to the cytoplasm in the control and to the lb in the ErbB4 deleted AEII. ErbB4 deletion let to a change in SP-B localization from lb in controls to the mvb in the homozygote negative lung.
ErbB4 deletion does not affect the structure of the sub cellular organelles in AE II. However, it interferes with the intracellular localization of SP-A and SP-B. The biologic relevance of these findings has to be elucidated. But it might be speculated that it has an effect on surfactant and overall lung function in these animals or is related to the chronic inflammation seen in these lungs.
ATS 2008 • Toronto International Conference
Filename: 955427
Abstract Category: 03.03 - PED - Developmental Lung Biology
