Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals
Jeffrey W. Tyner, … , Steven L. Brody, Michael J. Holtzman
Jeffrey W. Tyner, … , Steven L. Brody, Michael J. Holtzman
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):309-321. https://doi.org/10.1172/JCI25167.
View: Text | PDF
Research Article Pulmonology

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-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.

Authors

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

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Persistent EGFR activation on ciliated epithelial cells after viral infe...
Persistent EGFR activation on ciliated epithelial cells after viral infection. (A) Representative photomicrographs of airway sections from C57BL/6J mice obtained at 21 days after inoculation with SeV or an equivalent amount of SeV-UV and then immunostained for EGFR and p-EGFR as well as competition by 50-fold antigen (Ag) excess. Scale bar: 20 μm. (B) Representative photomicrographs of airway sections obtained from mice at 21 days after inoculation with SeV and then subjected to immunofluorescent staining for EGFR, β-tubulin, CCSP, and MUC5AC alone and in combination. Primary anti-EGFR Ab binding was detected by anti-CY3 Ab (red fluorescence) while others were detected by anti-FITC Ab (green fluorescence). Scale bar: 20 μm. Similar results were obtained for mice treated with SeV-UV.