| Autor: |
King, E. M., Holden, N. S., Rider, C. F., Siderovski, D. P., Gaunt, D. D., Bell, M. J., Heximer, S. P., Newton, R., Leigh, R., Giembycz, M. A., Johnson, M. |
| Jazyk: |
angličtina |
| Rok vydání: |
2011 |
| Předmět: |
|
| DOI: |
10.17615/qjpm-ac65 |
| Popis: |
In asthma and chronic obstructive pulmonary disease, activation of Gq-protein–coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)/long-acting β2-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 Gq 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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