ErbB4 regulates fetal surfactant phospholipid synthesis in primary fetal rat type II cells

Abstract

Insufficient fetal surfactant production leads to respiratory distress syndrome among preterm infants. Neuregulin signals the onset of fetal surfactant phospholipid synthesis through formation of erbB receptor dimers. We hypothesized that erbB4 downregulation in fetal type II epithelial cells will downregulate not only fetal surfactant phospholipid synthesis, but also affect proliferation and erbB receptor localization. We tested these hypotheses using small interfering RNA (siRNA) directed against the erbB4 gene to silence erbB4 receptor function in cultures of primary day 19 fetal rat lung type II cells. ErbB4 siRNA treatment inhibited erbB4 receptor protein expression, fibroblast-conditioned medium induced erbB4 phosphorylation, and fetal surfactant phospholipid synthesis. Cell proliferation, measured as thymidine incorporation, was also inhibited by erbB4 siRNA treatment. Downregulation of erbB4 receptor protein changed erbB1 localization at baseline and after stimulation, as determined by confocal microscopy and subcellular fractionation. We conclude that erbB4 is an important receptor in the control of fetal lung type II cell maturation.

Neuregulin Receptor ErbB4 Functions as a Transcriptional Cofactor for the Expression of Surfactant Protein B in the Fetal Lung

“…NRG-1 is secreted by lung fibroblasts (4), and the NRG receptor ErbB4 is expressed by fetal Type II cells (8,9). Both proteins play an important role in fetal Type II cell maturation (4,32), promoting the synthesis of fetal surfactant.…”

“…In fetal Type II cells, ErbB4 is a preferred dimerization partner for ErbB1, also known as epidermal growth factor receptor (EGFR) (8). ErbB4 actively regulates the most important functional maturation of the fetal Type II cell, namely, fetal surfactant synthesis (9). The deletion of ErbB4 leads to delayed fetal lung development (5) and structural and functional disturbances in the adult lung (10).…”

“…Therefore, the synthesis of surfactants by fetal pulmonary Type II cells is a crucial part of prenatal lung development (7), in preparation for the transition at birth from the intrauterine (aquatic) to the extrauterine (aerobic) environment. ErbB4, the signaling receptor for NRG, is the most prominent receptor dimerization partner in fetal Type II epithelial cells (8) and the down-regulation of ErbB4 inhibits fetal surfactant synthesis (9).…”

Human Epidermal Growth Factor Receptor Signaling in Acute Lung Injury

“…In the fetal lung, HER4 activation promotes ATII proliferation (66) and fetal lung growth, and genetic deletion of HER4 results in hypoplastic lungs similar to those observed in bronchopulmonary dysplasia (67). Surfactant production, a key physiological function of ATII cells, is regulated by HER4 in the developing lung (66,68). Given these critical roles for HER receptors in pulmonary organogenesis, these pathways are likely to play important roles in the setting of ALI and repair.…”

“…NRG-1 administration leads to HER2/ 3 activation, enhancing epithelial proliferation and differentiation (64) and stimulating fetal lung growth (63) via the MAPK and Akt pathways (65). In the fetal lung, HER4 activation promotes ATII proliferation (66) and fetal lung growth, and genetic deletion of HER4 results in hypoplastic lungs similar to those observed in bronchopulmonary dysplasia (67). Surfactant production, a key physiological function of ATII cells, is regulated by HER4 in the developing lung (66,68).…”