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Inhibition of Allergen-Induced Airway Remodeling in Smad 3-Deficient Mice¹

Annie V. Le^*,, Jae Youn Cho, Marina Miller, Shauna McElwain, Kirsti Golgotiu and David H. Broide^2,

^* Division of Allergy and Immunology, Scripps Clinic and Research Institute, La Jolla, CA 92037; and Department of Medicine, University of California, San Diego, La Jolla, CA 92093

Intracellular signaling pathways that converge on Smad 3 are used by both TGF- and activin A, key cytokines implicated in the process of fibrogenesis. To determine the role of Smad 3 in allergen-induced airway remodeling, Smad 3-deficient and wild-type (WT) mice were sensitized to OVA and challenged by repetitive administration of OVA for 1 mo. Increased levels of activin A and increased numbers of peribronchial TGF-1⁺ cells were detected in WT and Smad 3-deficient mice following repetitive OVA challenge. Smad 3-deficient mice challenged with OVA had significantly less peribronchial fibrosis (total lung collagen content and trichrome staining), reduced thickness of the peribronchial smooth muscle layer, and reduced epithelial mucus production compared with WT mice. As TGF- and Smad 3 signaling are hypothesized to mediate differentiation of fibroblasts to myofibroblasts in vivo, we determined the number of peribronchial myofibroblasts (Col-1⁺ and -smooth muscle actin⁺) as assessed by double-label immunofluorescence microscopy. Although the number of peribronchial myofibroblasts increased significantly in WT mice following OVA challenge, there was a significant reduction in the number of peribronchial myofibroblasts in OVA-challenged Smad 3-deficient mice. There was no difference in levels of eosinophilic airway inflammation or airway responsiveness in Smad 3-deficient compared with WT mice. These results suggest that Smad 3 signaling is required for allergen-induced airway remodeling, as well as allergen-induced accumulation of myofibroblasts in the airway. However, Smad 3 signaling does not contribute significantly to airway responsiveness.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from National Institutes of Health (T32 AI007469 (to A.V.L. and D.H.B.)) and R01 AI38425) and National Institute of Allergy and Infectious Diseases (U19 AI 70535; to D.H.B.).

² Address correspondence and reprint requests to Dr. David Broide, University of California, San Diego, Biomedical Sciences Building, Room 5090, 9500 Gilman Drive, La Jolla, CA 92093. E-mail address: dbroide{at}ucsd.edu

³ Abbreviations used in this paper: BALF, bronchoalveolar lavage fluid; AHR, airway responsiveness; Col-1, collagen-1; ECM, extracellular matrix; KO, knockout; MBP, major basic protein; MCh, methacholine; pSmad, phosphorylated Smad; SMA, smooth muscle actin.

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