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Am J Physiol Lung Cell Mol Physiol 279: L379-L389, 2000;
1040-0605/00 $5.00
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Vol. 279, Issue 2, L379-L389, August 2000

Transgenic overexpression of beta 2-adrenergic receptors in airway epithelial cells decreases bronchoconstriction

Dennis W. McGraw1, Susan L. Forbes1, Judith C. W. Mak2, David P. Witte3, Patricia E. Carrigan4, George D. Leikauf3, and Stephen B. Liggett1,5

Departments of 1 Medicine, 5 Molecular Genetics, and 4 Environmental Health, University of Cincinnati College of Medicine, Cincinnati 45267; 3 Department of Pathology, Children's Hospital Medical Center, Cincinnati, Ohio 45229; and 2 Department of Thoracic Medicine, National Heart and Lung Institute, London SW3 6LY, United Kingdom

Airway epithelial cells express beta 2-adrenergic receptors (beta 2-ARs), but their role in regulating airway responsiveness is unclear. With the Clara cell secretory protein (CCSP) promoter, we targeted expression of beta 2-ARs to airway epithelium of transgenic (CCSP-beta 2-AR) mice, thereby mimicking agonist activation of receptors only in these cells. In situ hybridization confirmed that transgene expression was confined to airway epithelium, and autoradiography showed that beta 2-AR density in CCSP-beta 2-AR mice was approximately twofold that of nontransgenic (NTG) mice. Airway responsiveness measured by whole body plethysmography showed that the methacholine dose required to increase enhanced pause to 200% of baseline (ED200) was greater for CCSP-beta 2-AR than for NTG mice (345 ± 34 vs. 157 ± 14 mg/ml; P < 0.01). CCSP-beta 2-AR mice were also less responsive to ozone (0.75 ppm for 4 h) because enhanced pause in NTG mice acutely increased to 77% over baseline (P < 0.05) but remained unchanged in the CCSP-beta 2-AR mice. Although both groups were hyperreactive to methacholine 6 h after ozone exposure, the ED200 for ozone-exposed CCSP-beta 2-AR mice was equivalent to that for unexposed NTG mice. These findings show that epithelial cell beta 2-ARs regulate airway responsiveness in vivo and that the bronchodilating effect of beta -agonists results from activation of receptors on both epithelial and smooth muscle cells.

G protein-coupled receptor; adenosine 3',5'-cyclic monophosphate; adenylyl cyclase; ozone


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