title: Amphiregulin-dependent mucous cell metaplasia in a model of nonallergic lung injury.
abstract: Proliferation and differentiation of the pulmonary epithelium after injury is a critical process in the defense against the external environment. Defects in this response can result in airway remodeling, such as mucus cell metaplasia (MCM), commonly seen in patients with chronic lung disease. We have previously shown that amphiregulin (AREG), a ligand to the epidermal growth factor receptor (EGFR), is induced during the repair/differentiation process elicited by naphthalene-induced lung injury. Thus, we hypothesized that AREG signaling plays an important role in epithelial proliferation and differentiation of the repairing airway. Mice deficient in AREG and lung epithelial EGFR were used to define roles for AREG-dependent EGFR signaling in airway repair and remodeling. We show that AREG and epithelial EGFR expression is dispensable to pulmonary epithelial repair after naphthalene-induced lung injury, but regulates secretory cell differentiation to a mucus-producing phenotype. We show that the pulmonary epithelium is the source of AREG, suggesting that naphthalene-induced MCM is mediated through an autocrine signaling mechanism. However, induction of MCM resulting from allergen exposure was independent of AREG. Our data demonstrate that AREG-dependent EGFR signaling in airway epithelial cells contributes to MCM in naphthalene-induced lung injury. We conclude that AREG may represent a determinant of nonallergic chronic lung diseases complicated by MCM.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Manzo
authors.forename: W Michael
authors.initials: WM
authors.lastname: Foster
authors.forename: Barry R
authors.initials: BR
authors.lastname: Stripp
mesh_terms: D066258:Amphiregulin; D000818:Animals; D002454:Cell Differentiation; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006023:Glycoproteins / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D055370:Lung Injury / Q000473:pathology*; D008679:Metaplasia / Q000473:pathology*; D051379:Mice; D009092:Mucous Membrane / Q000166:cytology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
chemical_list: D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D066246:ErbB Receptors