Role of neuregulin-1 beta in the developing lung.

Neuregulins play a critical role in the developing heart, nervous, and mammary systems. Neuregulin-1-induced cardiac, neuronal, and mammary differentiation is based on a cell-cell communication model, where the ligand neuregulin-1 is produced and secreted by one cell type, which does not express its receptors erbB3 and erbB4 and acts on neighboring cell types that do express these receptors. We proposed that neuregulin-1 affects fetal lung maturation through a similar mechanism. Immunostaining showed neuregulin-1 in fetal lung that increased in fibroblasts at the onset of surfactant synthesis. Neuregulin-1 beta was found to be secreted by the fetal lung fibroblast and stimulated type II cell surfactant synthesis. Both fetal lung fibroblast-conditioned media and neuregulin-1 stimulated erbB2 receptor phosphorylation in type II cells. The effects of neuregulin-1 and of fibroblast-conditioned media on both surfactant synthesis and type II cell erbB2 phosphorylation were specifically blocked by antibody to neuregulin-1. Thus, neuregulin-1 beta may control fetal lung maturation through mesenchymal-epithelial interactions in a paracrine mechanism similar to that described for the developing heart, brain, and mammary systems.