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Published ahead of print on August 29, 2007, doi:10.1164/rccm.200702-334OC

Am. J. Respir. Crit. Care Med., Volume 176, Number 10, November 2007, 974-982

A more recent version of this article appeared on November 15, 2007
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Submitted on February 27, 2007
Accepted on August 29, 2007

Transforming Growth Factor - {beta}1 Suppresses Airway Hyperresponsiveness in Allergic Airway Disease

John F Alcorn1*, Lisa M Rinaldi2, Elizabeth F Jaffe2, Mirjam van Loon2, Jason HT Bates2, Yvonne MW Janssen-Heininger1, and Charles G Irvin2

1 Department of Pathology, University of Vermont, Burlington, VT, USA, 2 Department of Medicine, University of Vermont, Burlington, VT, USA

* To whom correspondence should be addressed. E-mail: john.alcorn{at}med.uvm.edu.

Rationale: Asthma is characterized by increases in airway resistance, pulmonary remodeling, and lung inflammation. The cytokine transforming growth factor (TGF)-{beta} has been shown to have a central role in asthma pathogenesis and in mouse models of allergic airway disease. Objectives: To determine the contribution of TGF-[[beta] to airway hyperresponsiveness (AHR), we examined the time course, source, and isoform specificity of TGF-{beta} production in an in vivo mouse asthma model. To then elucidate the function of TGF-{beta} in AHR, inflammation, and pulmonary fibrosis we examined the effects of blocking TGF-{beta} signaling with neutralizing antibody. Methods: Mice were sensitized and challenged with ovalbumin (OVA) to establish allergic airway disease. TGF-{beta} activity was neutralized by intranasal administration of monoclonal antibody. Results: TGF-{beta}1 protein levels were increased in OVA challenged lungs versus naive controls and airway epithelial cells were shown to be a likely source of TGF-{beta}1. Additionally, TGF-{beta}1 levels were elevated in OVA-exposed IL-5 null mice, which fail to recruit eosinophils into the airways. Neutralization of TGF-{beta}1 with specific antibody had no significant effect on airway inflammation and eosinophilia, although anti-TGF-{beta}1 antibody enhanced OVA-induced AHR and suppressed pulmonary fibrosis. Conclusions: These data show that TGF-{beta}1 is the main TGF-{beta} isoform produced following OVA challenge with a likely cellular source being the airway epithelium. The effects of blocking TGF-{beta}1 signaling had differential effects on AHR, fibrosis, and inflammation. While TGF-{beta} neutralization may be beneficial to abrogating airway remodeling, it may be detrimental to lung function by increasing AHR.
Key words: Lung, Mice, Hypersensitivity, Cytokines




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