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Published ahead of print on January 3, 2008, doi:10.1164/rccm.200706-958OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 6, March 2008, 593-603

A more recent version of this article appeared on March 15, 2008
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Submitted on June 28, 2007
Accepted on January 3, 2008

TGF-{beta} Regulates House Dust Mite-induced Allergic Airway Inflammation but not Airway Remodeling

Ramzi Fattouh1, Gabriela Midence1, Katherine Arias1, Jill R Johnson1, Tina D Walker1, Susanna Goncharova1, Kailene P Souza2, Richard C Gregory2, Scott Lonning2, Jack Gauldie1, and Manel Jordana1*

1 Division of Respiratory Diseases and Allergy, Centre for Gene Therapeutics and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada, 2 Department of Cytokine Biology, Cell and Protein Therapeutics, Genzyme Corporation, Framingham, MA, USA

* To whom correspondence should be addressed. E-mail: jordanam{at}mcmaster.ca.

Rationale: It is now thought that both chronic airway inflammation and remodeling contribute significantly to airway dysfunction and clinical symptoms in allergic asthma. Transforming growth-factor-{beta} (TGF-{beta}) is a powerful regulator of both the tissue repair and inflammatory responses and numerous experimental and clinical studies suggest that it may play an integral role in the pathogenesis of asthma. Objectives: We investigated the role of TGF-{beta} in the regulation of allergic airway inflammation and remodeling using a mouse model of house dust mite (HDM)-induced chronic allergic airway disease. Methods: We have previously shown that intranasal administration of an HDM extract (5 days/week for 5 weeks) elicits robust Th2-polarized airway inflammation and remodeling that is associated with increased airway hyperreactivity. Here, Balb/c mice were similarly exposed to HDM and concurrently treated with a pan-specific TGF-{beta} neutralizing antibody. Measurements and Main Results: We observed that anti-TGF-{beta} treatment in the context of either continuous or intermittent HDM exposure had no effect on the development of HDM-induced airway remodeling. To further confirm these findings we also subjected SMAD3 KO mice to 5 weeks of HDM and observed that KO mice developed airway remodeling to the same extent as HDM-exposed littermate controls. Notably, TGF-{beta} neutralization exacerbated the eosinophilic infiltrate and led to increased airway hyperreactivity. Conclusions: Collectively, these data suggest that TGF-{beta} regulates HDM-induced chronic airway inflammation but not remodeling, and furthermore, caution against the use of therapeutic strategies aimed at interfering with TGF-{beta} activity in the treatment of this disease.
Key words: immunology, allergic asthma, mouse model, lung




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