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Published ahead of print on March 27, 2003, doi:10.1164/rccm.200205-468OC

Am. J. Respir. Crit. Care Med., Volume 167, Number 12, June 2003, 1711-1716

A more recent version of this article appeared on June 15, 2003
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Submitted on May 25, 2002
Accepted on March 25, 2003

Role of Neuregulin1{beta} in the Developing Lung

Christiane E.L. Dammann1*, Heber C Nielsen1, and Kermit L Carraway2

1 Pediatrics, Division of New Born Medicine, Tufts University School of Medicine, Boston, MA, USA; Pediatrics, Floating Hospital for Children, Boston, MA, USA, 2 Cell Biology, Harvard Medical School, Boston, MA, USA; Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: cdammann{at}tufts-nemc.org.

Neuregulins play a critical role in the developing heart, nervous and mammary systems. Neuregulin1-induced cardiac, neuronal, and mammary differentiation is based on a cell-cell communication model, where the ligand Neuregulin1 is produced and secreted by one cell type, which does not express its receptors erbB3 and erbB4, and acts on neighboring cell types which do express these receptors. We proposed that Neuregulin1 affects fetal lung maturation through a similar mechanism. Immunostaining showed Neuregulin1 in fetal lung which increased in fibroblasts at the onset of surfactant synthesis. Neuregulin1 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 Neuregulin1 stimulated erbB2 receptor phosphorylation in type II cells. The effects of Neuregulin1 and of fibroblast conditioned media on both surfactant synthesis and type II cell erbB2 phosphorylation were specifically blocked by antibody to Neuregulin1. Thus, NRG1{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 system.
Key words: Fetal lung development, fibroblast-pneumocyte-factor, fibroblast conditioned medium, erbB receptors, fibroblast-type II cell communication




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