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Laboratory and Animal Investigations |

Airway Mucosal Thickening and Bronchial Hyperresponsiveness Induced by Inhaled β2-Agonist in Mice*

Jun Tamaoki, MD, FCCP; Etsuko Tagaya, MD; Kiyomi Kawatani, MD; Junko Nakata, MD; Yumie Endo, MD; Atsushi Nagai, MD, FCCP
Author and Funding Information

*From the First Department of Medicine, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan.

Correspondence to: Jun Tamaoki, MD, FCCP, First Department of Medicine, Tokyo Women’s Medical University, 8-1 Kawada-Cho, Shinjuku, Tokyo 162-8666, Japan; e-mail: jtamaoki@chi.twmu.ac.jp



Chest. 2004;126(1):205-212. doi:10.1378/chest.126.1.205
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Background: Patients with chronic persistent asthma require frequent use of inhaled β2-agonist, which may result in aggravation of asthma symptoms. Our recent in vitro study has shown that β2-agonist stimulates the growth of human airway epithelial cell lines.

Study objective: To determine whether β2-agonist likewise affects airway epithelial cell proliferation in vivo and, if so, what the mechanism of action is, we examined the effect of salbutamol on the morphology of murine airways.

Methods: Seventy-two BALB/c mice were administered aerosolized salbutamol using “flow-through” nose-only inhalation chambers at daily doses of 0.2 to 20 μg for up to 6 weeks. Morphology of tracheal mucosa, labeling of epithelial cells with 5-bromo-2′-deoxyuridine (BrdU), and bronchial responsiveness were assessed.

Results: Exposure to salbutamol increased the thickness of tracheal epithelial layer and the number of BrdU-positive epithelial cells in a dose- and time-dependent manner: the values in mice receiving 20 μg salbutamol for 6 weeks were 247% and 642%, respectively, of those in control animals receiving saline solution alone. These effects were inhibited by the mitogen-activated protein (MAP) kinase kinase inhibitors PD98059 and U0126. Salbutamol also caused a decrease in the provocative concentration of methacholine to achieve 400% of baseline enhanced pause. Combined treatment with inhaled budesonide attenuated salbutamol-induced airway morphologic changes and bronchial hyperresponsiveness.

Conclusion: β2-agonist stimulates proliferation of airway epithelial cells and produces airway wall thickening in vivo via MAP kinase-dependent pathway, and these effects are prevented by inhaled corticosteroid.

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