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Transforming Growth Factor-1 Suppresses Airway Hyperresponsiveness in Allergic Airway Disease

¹ Department of Pathology and ² Department of Medicine, University of Vermont, Burlington, Vermont

Correspondence and requests for reprints should be addressed to John F. Alcorn, Ph.D., 223 HSRF, Department of Pathology, University of Vermont, Burlington, VT 05405. 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)- 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- to airway hyperresponsiveness (AHR), we examined the time course, source, and isoform specificity of TGF- production in an in vivo mouse asthma model. To then elucidate the function of TGF- in AHR, inflammation, and pulmonary fibrosis, we examined the effects of blocking TGF- signaling with neutralizing antibody.

Methods: Mice were sensitized and challenged with ovalbumin (OVA) to establish allergic airway disease. TGF- activity was neutralized by intranasal administration of monoclonal antibody.

Measurements and Main Results: TGF-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-1. In addition, TGF-1 levels were elevated in OVA-exposed IL-5–null mice, which fail to recruit eosinophils into the airways. Neutralization of TGF-1 with specific antibody had no significant effect on airway inflammation and eosinophilia, although anti–TGF-1 antibody enhanced OVA-induced AHR and suppressed pulmonary fibrosis.

Conclusions: These data show that TGF-1 is the main TGF- isoform produced after OVA challenge, with a likely cellular source being the airway epithelium. The effects of blocking TGF-1 signaling had differential effects on AHR, fibrosis, and inflammation. While TGF- neutralization may be beneficial to abrogating airway remodeling, it may be detrimental to lung function by increasing AHR.

Key Words: lung • mice • hypersensitivity • cytokines

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Transforming growth factor (TGF)-1 is known to play a critical role in promoting pulmonary remodeling; however, its contribution to airway hyperresponsiveness (AHR) is less well defined. What This Study Adds to the Field TGF-1 is the predominant TGF- isoform produced in a mouse asthma model and neutralization of TGF-1 results in less fibrosis and increased AHR.

 

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