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 9

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Evidence of cilia-to-goblet cell transdifferentiation in human epithelia...
Evidence of cilia-to-goblet cell transdifferentiation in human epithelial cells in vivo and in vitro. (A) Representative photomicrographs from lung sections obtained from COPD patients and immunostained for β-tubulin and MUC5AC, counterstained with DAPI, and viewed with immunofluorescence microscopy (left panel) or immunostained for β-tubulin and MUC5AC or CCSP and MUC5AC and viewed with laser confocal scanning microscopy (middle and right panels). Arrows and outlines indicate goblet cells that express MUC5AC (g), Clara cells that express CCSP (cc), cilia-goblet cells that coexpress β-tubulin and MUC5AC (cig), and goblet cells that coexpress CCSP (ccg). (B) Representative photomicrographs of human large airway epithelial cells (hLAECs) cultured from COPD patients, incubated with IL-13 (100 ng/ml) for 5 days, and then immunostained for β-tubulin (red) and MUC5AC (green). (C) Representative photomicrographs of hLAECs cultured from control (non-COPD) subjects, incubated with IL-13 for 1 day, immunostained as in B, and then viewed with laser confocal scanning microscopy in x-y axis and z axis views. In B and C, arrows indicate cells that immunostained for both γ-tubulin and MUC5AC. Scale bar: 20 μm.