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Role of Insulin-like Growth Factor Binding Protein-3 in Allergic Airway Remodeling

¹ Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine; University of Pittsburgh, Pittsburgh, Pennsylvania; and ² Department of Medicine; Allergy, Pulmonary, and Critical Care Section, University of Wisconsin, Madison, Wisconsin

Correspondence and requests for reprints should be addressed to Carol A. Feghali-Bostwick, Ph.D., University of Pittsburgh, Division of Pulmonary, Allergy, and Critical Care Medicine, MUH NW 628, 3459 Fifth Ave., Pittsburgh, PA 15213. E-mail: feghalica{at}upmc.edu

Rationale: The hallmarks of allergic asthma are airway inflammation, obstruction, and remodeling. Airway remodeling may lead to irreversible airflow obstruction with increased morbidity and mortality. Despite advances in the treatment of asthma, the mechanisms underlying airway remodeling are still poorly understood. We reported that insulin-like growth factor (IGF) binding proteins (IGFBPs) contribute to extracellular matrix deposition in idiopathic pulmonary fibrosis; however, their contribution to airway remodeling in asthma has not been established.

Objectives: We hypothesized that IGFBP-3 is overexpressed in asthma and contributes to airway remodeling.

Methods: We evaluated levels of IGFBP-3 in tissues and bronchoalveolar lavage fluid from patients with asthma at baseline and 48 hours after allergen challenge, in reparative epithelium in an in vitro wounding assay, and in conditioned media from cytokine- and growth factor–stimulated primary epithelial cells.

Measurements and Main Results: IGFBP-3 levels and distribution were evaluated by Western blot, ELISA, and immunofluorescence. IGFBP-3 is increased in vivo in the airway epithelium of patients with asthma compared with normal control subjects. The concentration of IGFBP-3 is increased in the bronchoalveolar lavage fluid of patients with asthma after allergen challenge, its levels are increased in reparative epithelium in an in vitro wounding assay and in the conditioned medium of primary airway epithelial cell cultures stimulated with IGF-I.

Conclusions: Our results suggest that one mechanism of allergic airway remodeling is through the secretion of the profibrotic IGFBP-3 from IGF-I–stimulated airway epithelial cells during allergic inflammation.

Key Words: asthma • bronchoalveolar lavage • primary epithelial cells • insulin-like growth factor binding protein • fibrosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Allergic airway remodeling causes significant morbidity and mortality among patients with asthma and currently there are no effective therapies available to prevent or reverse this process. What This Study Adds to the Field Our results suggest that one mechanism of allergic airway remodeling is through the secretion of profibrotic insulin-like growth factor binding protein-3 (IGFBP-3) from insulin-like growth factor-1 (IGF-1) stimulated airway epithelial cells during allergic inflammation.