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Transforming Growth Factor-β Regulates House Dust Mite–induced Allergic Airway Inflammation but Not Airway Remodeling

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

Correspondence and requests for reprints should be addressed to Manel Jordana, M.D., Ph.D., Professor, Department of Pathology and Molecular Medicine, Head, Division of Respiratory Diseases and Allergy, MDCL 4013, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada. E-mail: jordanam{at}mcmaster.ca

Rationale: It is now believed that both chronic airway inflammation and remodeling contribute significantly to airway dysfunction and clinical symptoms in allergic asthma. Transforming growth factor (TGF)-β 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-β 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 d/wk for 5 wk) 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-β neutralizing antibody.

Measurements and Main Results: We observed that anti–TGF-β 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 knockout mice to 5 weeks of HDM and observed that knockout mice developed airway remodeling to the same extent as HDM-exposed littermate controls. Notably, TGF-β neutralization exacerbated the eosinophilic infiltrate and led to increased airway hyperreactivity.

Conclusions: Collectively, these data suggest that TGF-β regulates HDM-induced chronic airway inflammation but not remodeling, and furthermore, caution against the use of therapeutic strategies aimed at interfering with TGF-β activity in the treatment of this disease.

Key Words: immunology • allergic asthma • mouse model • lung

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Transforming growth factor (TGF)-β appears to play a prominent role in the development of airway remodeling, a recognized feature of chronic allergic asthma. What This Study Adds to the Field This research suggests that airway remodeling may be independent of TGF-β, and that therapeutic strategies to prevent remodeling through TGF-β interference may have detrimental effects by increasing eosinophilic infiltration and airway hyperreactivity.