title: Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals.
abstract: Epithelial hyperplasia and metaplasia are common features of inflammatory and neoplastic disease, but the basis for the altered epithelial phenotype is often uncertain. Here we show that long-term ciliated cell hyperplasia coincides with mucous (goblet) cell metaplasia after respiratory viral clearance in mouse airways. This chronic switch in epithelial behavior exhibits genetic susceptibility and depends on persistent activation of EGFR signaling to PI3K that prevents apoptosis of ciliated cells and on IL-13 signaling that promotes transdifferentiation of ciliated to goblet cells. Thus, EGFR blockade (using an irreversible EGFR kinase inhibitor designated EKB-569) prevents virus-induced increases in ciliated and goblet cells whereas IL-13 blockade (using s-IL-13Ralpha2-Fc) exacerbates ciliated cell hyperplasia but still inhibits goblet cell metaplasia. The distinct effects of EGFR and IL-13 inhibitors after viral reprogramming suggest that these combined therapeutic strategies may also correct epithelial architecture in the setting of airway inflammatory disorders characterized by a similar pattern of chronic EGFR activation, IL-13 expression, and ciliated-to-goblet cell metaplasia.
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.forename: Edy Y
authors.initials: EY
authors.lastname: Kim
authors.forename: Kyotaro
authors.initials: K
authors.lastname: Ide
authors.forename: Mark R
authors.initials: MR
authors.lastname: Pelletier
authors.forename: William T
authors.initials: WT
authors.lastname: Roswit
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Morton
authors.forename: John T
authors.initials: JT
authors.lastname: Battaile
authors.forename: Anand C
authors.initials: AC
authors.lastname: Patel
authors.forename: G Alexander
authors.initials: GA
authors.lastname: Patterson
authors.forename: Mario
authors.initials: M
authors.lastname: Castro
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Spoor
authors.forename: Yingjian
authors.initials: Y
authors.lastname: You
authors.forename: Steven L
authors.initials: SL
authors.lastname: Brody
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia; D018793:Interleukin-13 / Q000378:metabolism*; D008679:Metaplasia; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055271:Mucin 5AC; D009077:Mucins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D014780:Viruses / Q000378:metabolism
chemical_list: D018793:Interleukin-13; C524678:MUC5AC protein, human; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D009077:Mucins; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors