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Beta-agonist-associated reduction in RGS5 expression promotes airway smooth muscle hyper-responsiveness.

ABSTRACT: Although short-acting and long-acting inhaled ?(2)-adrenergic receptor agonists (SABA and LABA, respectively) relieve asthma symptoms, use of either agent alone without concomitant anti-inflammatory drugs (corticosteroids) may increase the risk of disease exacerbation in some patients. We found previously that pretreatment of human precision-cut lung slices (PCLS) with SABA impaired subsequent ?(2)-agonist-induced bronchodilation, which occurred independently of changes in receptor quantities. Here we provide evidence that prolonged exposure of cultured human airway smooth muscle (HuASM) cells to ?(2)-agonists directly augments procontractile signaling pathways elicited by several compounds including thrombin, bradykinin, and histamine. Such treatment did not increase surface receptor amounts or expression of G proteins and downstream effectors (phospholipase C? and myosin light chain). In contrast, ?-agonists decreased expression of regulator of G protein signaling 5 (RGS5), which is an inhibitor of G-protein-coupled receptor (GPCR) activity. RGS5 knockdown in HuASM increased agonist-evoked intracellular calcium flux and myosin light chain (MLC) phosphorylation, which are prerequisites for contraction. PCLS from Rgs5(-/-) mice contracted more to carbachol than those from WT mice, indicating that RGS5 negatively regulates bronchial smooth muscle contraction. Repetitive ?(2)-agonist use may not only lead to reduced bronchoprotection but also to sensitization of excitation-contraction signaling pathways as a result of reduced RGS5 expression.

SUBMITTER: Yang Z

PROVIDER: S-EPMC3064200 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Beta-agonist-associated reduction in RGS5 expression promotes airway smooth muscle hyper-responsiveness.

Yang Zhao Z Cooper Philip R PR Damera Gautam G Mukhopadhyay Indranil I Cho Hyeseon H Kehrl John H JH Panettieri Reynold A RA Druey Kirk M KM

The Journal of biological chemistry 20110129 13

Although short-acting and long-acting inhaled β(2)-adrenergic receptor agonists (SABA and LABA, respectively) relieve asthma symptoms, use of either agent alone without concomitant anti-inflammatory drugs (corticosteroids) may increase the risk of disease exacerbation in some patients. We found previously that pretreatment of human precision-cut lung slices (PCLS) with SABA impaired subsequent β(2)-agonist-induced bronchodilation, which occurred independently of changes in receptor quantities. H ...[more]

PMID: 21278382

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Project description:Selective stimulation of IL-4 receptor on smooth muscle induces airway hyper-responsiveness in mice. Abstract: Production of the cytokines IL-4 and IL-13 is increased in both human asthma and mouse asthma models and Stat6 activation by the common IL-4/IL-13R drives most mouse model pathophysiology, including airway hyperresponsiveness (AHR). However, the precise cellular mechanisms through which IL-4Rα induces AHR remain unclear. Overzealous bronchial smooth muscle constriction is thought to underlie AHR in human asthma, but the smooth muscle contribution to AHR has never been directly assessed. Furthermore, differences in mouse vs. human airway anatomy and observations that selective IL-13 stimulation of Stat6 in airway epithelium induces murine AHR raise questions about the importance of direct IL-4R effects on smooth muscle in murine asthma models and relevance of these models to human asthma. Using transgenic mice in which smooth muscle is the only cell type that expresses or fails to express IL-4Rα, we demonstrate that direct smooth muscle activation by IL-4, IL-13, or allergen is sufficient, but not necessary, to induce AHR and show that 5 genes known to promote smooth muscle migration, proliferation and contractility are activated by IL-13 in smooth muscle in vivo. These observations demonstrate that IL-4Rα promotes AHR through multiple mechanisms and provide a model for testing smooth muscle-directed asthma therapeutics. For the microarray aspect of of the study, there were three groups of mice: 1. IL4R gene knockout (KO) mice 2. WT mice 3. IL4R KO mice that were also transgenic for a gene construct that expressed IL4R under the control of the smooth muscle-specific promoter from the SMP8 gene All mice were subjected to intratracheal IL13 exposure for 7 days, and whole lung RNA was prepared for microarray analysis 24 hours after the last instillation. Per treatment and genotype: Two RNA pools were made from four mice each. These were labeled and hybridized to make a total of 6 microarrays. RNA was labeled with the standard Affymetrix 3' labeling protocol to make cDNA that was hybridized to Mouse MOE 430 plus 2.0 GeneChips. Gene transcripts were identified that differed in their relative expression as a function of IL4R expression on the smooth muscle cells.

Dataset Information

Beta-agonist-associated reduction in RGS5 expression promotes airway smooth muscle hyper-responsiveness.

Publications

Beta-agonist-associated reduction in RGS5 expression promotes airway smooth muscle hyper-responsiveness.

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