Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals

Jeffrey W. Tyner, Edy Y. Kim, Kyotaro Ide, Mark R. Pelletier, William T. Roswit, Jeffrey D. Morton, John T. Battaile, Anand C. Patel, G. Alexander Patterson, Mario Castro, Melanie S. Spoor, Yingjian You, Steven L. Brody, Michael J. Holtzman

Research output: Contribution to journalArticle

184 Scopus citations

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-13Rα2-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.

Original languageEnglish
Pages (from-to)309-321
Number of pages13
JournalJournal of Clinical Investigation
Volume116
Issue number2
DOIs
StatePublished - Feb 1 2006

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    Tyner, J. W., Kim, E. Y., Ide, K., Pelletier, M. R., Roswit, W. T., Morton, J. D., Battaile, J. T., Patel, A. C., Patterson, G. A., Castro, M., Spoor, M. S., You, Y., Brody, S. L., & Holtzman, M. J. (2006). Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals. Journal of Clinical Investigation, 116(2), 309-321. https://doi.org/10.1172/JCI25167