Transgenic overexpression of beta(2)-adrenergic receptors in airway epithelial cells decreases bronchoconstriction.
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 (ED(200)) 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 ED(200) 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.
Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
D W
DW
McGraw
S L
SL
Forbes
J C
JC
Mak
D P
DP
Witte
P E
PE
Carrigan
G D
GD
Leikauf
S B
SB
Liggett
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016084:Bronchoconstriction / Q000187:drug effects / Q000235:genetics*; D015232:Dinoprostone / Q000032:analysis; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018721:Muscarinic Agonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000032:analysis; D010126:Ozone / Q000494:pharmacology; D010993:Plethysmography, Whole Body; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis* / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D019076:Transgenes / Q000235:genetics*; D014598:Uteroglobin
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D018721:Muscarinic Agonists; D011506:Proteins; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D011993:Recombinant Fusion Proteins; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; D009569:Nitric Oxide; D010126:Ozone; D014598:Uteroglobin; D015232:Dinoprostone