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.
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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

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Figure 8

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Identification and blockade of cilia-to-goblet cell transdifferentiation...
Identification and blockade of cilia-to-goblet cell transdifferentiation in vitro and in vivo. (A) Representative photomicrographs of airway sections obtained from mice at 21 days after SeV inoculation and subjected to confocal immunofluorescence microscopy for β-tubulin (green) and MUC5AC (red). Arrows indicate ciliated cells staining for β-tubulin (ci), goblet cells staining for MUC5AC (g), and cells staining for both β-tubulin and MUC5AC (cig). (B) Representative photomicrographs of airway sections obtained as in A but immunostained for p-EGFR (red) and MUC5AC (green). Arrows indicate ciliated cells staining for p-EGFR (ci), goblet cells staining for MUC5AC (g), and cells staining for both p-EGFR and MUC5AC (cig). (C) Representative photomicrographs of airway sections obtained as in A but immunostained for CCSP (green) and MUC5AC (red). Arrows indicate cells staining for CCSP (cc) or CCSP and MUC5AC (ccg). Scale bars: 20 μm. (D) Quantitative analysis of MUC5AC-expressing cells that also immunostained for CCSP or β-tubulin. (E) Real-time PCR analysis of lung IL-13, mCLCA3, and MUC5AC mRNA levels corrected for GAPDH control level at indicated times after SeV inoculation. (F) Quantitative analysis of β-tubulin, CCSP, and Muc5AC immunostaining in mice inoculated with SeV and treated with sIL-13Rα2-Fc or control IgG on days 12, 14, 17, and 20 after inoculation. Values represent mean ± SEM *Significant difference from corresponding SeV-UV control for D and E or IgG treatment for F.