Am. J. Respir. Cell Mol. Biol.,
Volume 22, Number 4, April, 2000 432-440
Neuregulin-1 and Human Epidermal Growth Factor Receptors 2 and 3 Play a Role in Human Lung Development In Vitro
Neil V.
Patel,
Michael J.
Acarregui,
Jeanne M.
Snyder,
Jonathan M.
Klein,
Mark X.
Sliwkowski,
and
Jeffrey A.
Kern
Departments of Internal Medicine, Pediatrics, and Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, Iowa;
and Genentech, Inc., South San Francisco, California
The human epidermal growth factor receptor (HER) family
consists of four distinct receptors: HER1 (epidermal growth
factor receptor), HER2, HER3, and HER4. Their specific activating ligands are collectively known as neuregulins (NRG). We
hypothesized that one member of the NRG family, NRG-1, and
the HER family would play a role in fetal lung development. To
test this hypothesis, we defined NRG-1 and HER gene expression in mid-trimester human fetal lung tissue. HER2 and HER3
messenger RNA and protein were detected in the fetal lung,
but HER4 expression was not detected. Immunohistochemical
staining of fetal lung tissue localized HER2 and HER3 protein to
the developing lung epithelium. NRG-1 expression was not
found in freshly isolated human fetal lung, but it was observed
in fetal lung explants after 2 d of explant culture. Immunohistochemistry of cultured human fetal lung explants revealed that NRG-1 protein was also expressed in pulmonary epithelial cells. Exposing human fetal lung to recombinant NRG-1 activated the HER receptor complex as measured by ~ 4-fold increases in receptor phosphotyrosine content. In addition,
NRG-1 increased explant epithelial cell volume density ~ 2-fold
(P < 0.03); increased epithelial cell proliferation ~ 2-fold, as
determined by bromodeoxyuridine labeling (P = 0.002); and
reduced surfactant protein-A (SP-A) levels by 53% (P < 0.05).
These data are consistent with an autocrine regulatory process
mediated by NRG-1 activation of HER2/HER3 heterodimers expressed on developing human fetal lung epithelial cells. Receptor activation results in increased lung epithelial cell proliferation and volume density, and decreased SP-A production, a
marker of type II pneumocyte differentiation.
