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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Johnson, Malcolm Holden, Neil S. Giembycz, Mark A. Bell, Matthew J. Newton, Robert Rider, Christopher F. Leigh, Richard Heximer, Scott P. King, Elizabeth M. Gaunt, David D. Siderovski, David P. |
| Description | Author Affiliation: Holden NS ( Airways Inflammation Research Group, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1.); |
| Abstract | In asthma and chronic obstructive pulmonary disease, activation of G(q)-protein-coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)/long-acting ß(2)-adrenoceptor agonist (LABA) combination therapies, which are more efficacious than either monotherapy alone. In primary human airway smooth muscle cells, glucocorticoid/LABA combinations synergistically induce the expression of regulator of G-protein signaling 2 (RGS2), a GTPase-activating protein that attenuates G(q) signaling. Functionally, RGS2 reduced intracellular free calcium flux elicited by histamine, methacholine, leukotrienes, and other spasmogens. Furthermore, protection against spasmogen-increased intracellular free calcium, following treatment for 6 h with LABA plus corticosteroid, was dependent on RGS2. Finally, Rgs2-deficient mice revealed enhanced bronchoconstriction to spasmogens and an absence of LABA-induced bronchoprotection. These data identify RGS2 gene expression as a genomic mechanism of bronchoprotection that is induced by glucocorticoids plus LABAs in human airway smooth muscle and provide a rational explanation for the clinical efficacy of inhaled corticosteroid (glucocorticoid)/LABA combinations in obstructive airways diseases. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 49 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-12-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Adrenergic Beta-2 Receptor Agonists Pharmacology Bronchoconstriction Drug Effects Glucocorticoids RGS Proteins Genetics Albuterol Analogs & Derivatives Animals Blotting, Western Physiology Budesonide Calcium Metabolism Cell Line Cells, Cultured Dexamethasone Drug Synergism Ethanolamines Formoterol Fumarate Gene Expression Lung Cytology Mice Mice, Inbred C57BL Mice, Knockout Muscle, Smooth Myocytes, Smooth Muscle RNA Interference Reverse Transcriptase Polymerase Chain Reaction Salmeterol Xinafoate Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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