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Published online before print July 24, 2008
Eur Respir J 2008, doi:10.1183/09031936.00166907
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ORIGINAL ARTICLE

The epidermal growth factor receptor mediates allergic airway remodeling in the rat

M. Tamaoka 1, M. Hassan 1, T. McGovern 1, D. Ramos-Barbón 1, J. Taisuke 1, Y. Yoshizawa 2, B. Tolloczko 1, Q. Hamid 1, J.G. Martin 1*

1 Meakins-Christie Laboratories, Dept of Medicine, McGill University, Montréal, Québec, H2X 2P2 Canada
2 Dept of Integrative Pulmonology, Tokyo Medical and Dental University, Tokyo, Japan

* To whom correspondence should be addressed. E-mail: james.martin{at}mcgill.ca.


  Abstract

The chronicity of bronchial asthma is attributed to persistent airway inflammation and to a variety of structural changes, or remodeling, that includes smooth muscle and goblet cell hyperplasia.

To investigate the mechanisms of airway remodeling we used an established allergen (OVA)-driven rodent model (BN rat).

BN rats were sensitized to ovalbumin and challenged 3 times at 5 day intervals to evoke airway remodeling. The effects of an epidermal growth factor (EGF) receptor inhibitor, AG1478, and a cysteinyl leukotriene-1 receptor antagonist, montelukast, were tested on epithelial and ASM cell proliferation in vivo in response to repeated OVA challenge. Three challenges with leukotriene D4 (LTD4) were given to examine their effects on remodeling with and without AG1478 pre-treatment.

OVA challenges caused ASM hyperplasia with an increase in mass and epithelial cell proliferation and goblet cell proliferation. AG1478 prevented the changes as did montelukast. Multiple OVA challenges increased heparin-binding EGF-like growth factor (HB-EGF) but not EGF expression by airway epithelium. LTD4 recapitulated the changes in remodeling induced by OVA and this was blocked by AG1478.

Allergen induced airway epithelial and ASM remodeling is mediated by cysteinyl leukotrienes via the cys-LT1R with downstream effects on the EGFR axis.

Keywords:  Allergy, inflammation, lung, signal transduction




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