Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals.
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.
Tyner
Jeffrey W
JW
Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Kim
Edy Y
EY
Ide
Kyotaro
K
Pelletier
Mark R
MR
Roswit
William T
WT
Morton
Jeffrey D
JD
Battaile
John T
JT
Patel
Anand C
AC
Patterson
G Alexander
GA
Castro
Mario
M
Spoor
Melanie S
MS
You
Yingjian
Y
Brody
Steven L
SL
Holtzman
Michael J
MJ
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
D018793:Interleukin-13; C524678:MUC5AC protein, human; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D009077:Mucins; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors