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 +13 more
TLDR
It is shown that long-term ciliated cell hyperplasia coincides with mucous (goblet) cell metaplasia after respiratory viral clearance in mouse airways, and 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.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-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.read more
Citations
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Epithelial repair mechanisms in the lung
TL;DR: The recovery of an intact epithelium following lung injury is critical for restoration of lung homeostasis and several key signaling pathways are important in regulating these processes, including sonic hedgehog, Rho GTPases, MAP kinase pathways, STAT3, and Wnt.
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Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease.
Edy Y. Kim,John T. Battaile,Anand C. Patel,Yingjian You,Eugene Agapov,Mitchell H. Grayson,Loralyn A. Benoit,Derek E. Byers,Yael G. Alevy,Jennifer Tucker,Suzanne Swanson,Rose M. Tidwell,Jeffrey W. Tyner,Jeffrey D. Morton,Mario Castro,Deepika Polineni,G. Alexander Patterson,Reto A. Schwendener,John Allard,Gary Peltz,Michael J. Holtzman +20 more
TL;DR: It is found that this type of disease arises independently of an adaptive immune response and is driven instead by interleukin-13 produced by macrophages that have been stimulated by CD1d-dependent T cell receptor–invariant natural killer T (NKT) cells.
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Pathobiology of cigarette smoke-induced chronic obstructive pulmonary disease
Toshinori Yoshida,Rubin M. Tuder +1 more
TL;DR: The authors provide an updated insight into the molecular and cellular pathobiology of COPD based on human and/or animal data.
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Mucins, Mucus, and Sputum*
Judith A. Voynow,Bruce K. Rubin +1 more
TL;DR: Mucin glycoprotein overproduction and hypersecretion are common features of chronic inflammatory airway disease, and this has been the underlying rationale to investigate the mechanisms of mucin gene regulation and mucin secretion.
Journal ArticleDOI
Animal models of chronic obstructive pulmonary disease
TL;DR: None of the models reproduces the exact changes seen in humans, but cigarette smoke-induced disease appears to come the closest, and genetically modified animals also, in some instances, shed light on processes that appear to play a role.
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