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1 Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
2 Department of Otolaryngology, Head and Neck Surgery, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA
* To whom correspondence should be addressed. E-mail: joseph-zabner{at}uiowa.edu.
A clinical case documented a reversible change in airway epithelial differentiation that coincided with the initiation and discontinuation of trastuzumab, an anti-erbB2 antibody. This prompted the investigation into whether blocking the erbB2 receptor alters differentiation of the airway epithelium. If so, blocking or exogenously stimulating the receptor would lead to consequences on differentiation. To test this hypothesis, an in vitro model of well-differentiated human airway epithelia was treated with trastuzumab or heregulin-
, an erbB ligand. In addition, co-culturing with human lung fibroblasts tested whether in vivo subepithelial fibroblasts function as an endogenous source of ligands able to activate erbB receptors expressed by the overlying epithelial cells. Epithelia were stained with hematoxylin and eosin and used for morphometric analysis. Trastuzumab treatment decreased the ciliated cell number by 49% and increased the metaplastic, flat cell number by 640%. Heregulin- treatment increased epithelial height, decreased the number of metaplastic and non-ciliated columnar cells while it increased the goblet cell number. We found that normal human lung fibroblasts express transforming growth factor-, heparin binding-epidermal-like growth factor, epiregulin, heregulin-, and amphiregulin, all of which are erbB ligands. Co-cultures of airway epithelia with primary fibroblasts increased epithelial height comparable to that achieved following heregulin- treatment. These data show that erbB2 stimulation is required for maintaining epithelial differentiation. Furthermore, the mesenchyme underlying the airway epithelium secretes a variety of erbB ligands that might direct various pathways of epithelial differentiation.
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