Regulator of G protein signaling 2 is a key modulator of airway hyperresponsiveness

Xie, Yan; Jiang, Haihong; Nguyen, Hoa; Song, Jia; Berro, A.I.; Panettieri, Reynold A.; Wolff, Dennis W.; Abel, Peter W.; Casale, Thomas B.; Tu, Yaping

doi:10.1016/j.jaci.2012.05.004

Cited by 42 publications

(71 citation statements)

References 48 publications

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“…Here, one study identified increased RGS4 as being inhibitory to ASM contractility in severe, recalcitrant asthma but interestingly promoting a proliferative phenotype of ASM (49). Separately, RGS2, an inhibitor of multiple G q -coupled receptors expressed in human and murine ASM, is downregulated in ovalbumin-sensitized/ challenged mice as well as in the lungs of asthmatic humans (340). These emerging data point to multiple novel strategies to reduce bronchoconstriction while enhancing bronchodilation.…”

Section: Asm [Ca 2ϩ ] I and Contractilitymentioning

confidence: 92%

“…Certainly, much work is needed to identify techniques or complementary drugs to target specific GRK isoforms or ␤-arrestins to enhance or maintain the functionality of particular bronchodilator therapies, be it ␤ 2 -agonists or bitter tastants and other novel therapies in the future. Along the lines of GRKs and ␤-arrestins, is the increasing recognition that regulators of G-protein signaling (RGS) may play a role in airway contractility (as well as remodeling) (49,64,289,290,340,343). A specific RGS usually prevents the continued activation of multiple G proteins, and thus upregulation or downregulation of RGS can have broad effects.…”

Section: Asm [Ca 2ϩ ] I and Contractilitymentioning

confidence: 99%

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Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Prakash

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

172

154

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Prakash YS. Airway smooth muscle in airway reactivity and remodeling: what have we learned? Am J Physiol Lung Cell Mol Physiol 305: L912-L933, 2013. First published October 18, 2013 doi:10.1152/ajplung.00259.2013.-It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca 2ϩ ]i contractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro-vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM "activity" result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis.

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Section: Asm [Ca 2ϩ ] I and Contractilitymentioning

confidence: 92%

Section: Asm [Ca 2ϩ ] I and Contractilitymentioning

confidence: 99%

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Prakash

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

172

154

View full text Add to dashboard Cite

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“…unless otherwise indicated. RGS2 expression to protect against bronchoconstriction and, potentially, the proinflammatory effects of mediators such as histamine and acetylcholine (Holden et al, , 2014Xie et al, 2012). Furthermore, RGS2 expression is synergistically enhanced by LABAs, or other cAMP-elevating compounds, in combination with glucocorticoids in human bronchial epithelial and ASM cells (Holden et al, , 2014.…”

Section: Tablementioning

confidence: 99%

“…Because this also occurs with glucocorticoid-induced genes, in vivo correlates may account for the benefits of ICS/LABA therapy Kaur et al, 2008). For example, regulator of G-protein signaling 2 (RGS2), which terminates signaling from the heterotrimeric G protein Ga q (Heximer, 2004;Kimple et al, 2009), is bronchoprotective in vivo and may also attenuate cytokine release (Holden et al, , 2014Xie et al, 2012). Importantly, in human airway smooth muscle (ASM) and bronchial epithelial cells, RGS2 expression is induced by LABAs and this is synergistically enhanced and prolonged by glucocorticoids (Holden et al, , 2014.…”

Section: Introductionmentioning

confidence: 99%

Superiority of Combined Phosphodiesterase PDE3/PDE4 Inhibition over PDE4 Inhibition Alone on Glucocorticoid- and Long-Acting β₂-Adrenoceptor Agonist–Induced Gene Expression in Human Airway Epithelial Cells

et al. 2014

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Glucocorticoids, also known as corticosteroids, induce effector gene transcription as a part of their anti-inflammatory mechanisms of action. Such genomic effects can be significantly enhanced by long-acting b 2 -adrenoceptor agonists (LABAs) and may contribute to the clinical superiority of inhaled corticosteroid (ICS)/LABA combinations in asthma and chronic obstructive pulmonary disease (COPD) over ICSs alone. Using models of cAMP-and glucocorticoid-induced transcription in human bronchial epithelial BEAS-2B cells, we show that combining inhibitors of phosphodiesterase (PDE) 3 and PDE4 provides greater benefits compared with inhibiting either PDE alone. In respect to cAMP-dependent transcription, inhibitors of PDE3 (siguazodan, cilostazol) and PDE4 (rolipram, GSK256066, roflumilast N-oxide) each sensitized to the LABA, formoterol. This effect was magnified by dual PDE3 and PDE4 inhibition. Siguazodan plus rolipram was also more effective at inducing cAMP-dependent transcription than either inhibitor alone. Conversely, the concentration-response curve describing the enhancement of dexamethasone-induced, glucocorticoid response element-dependent transcription by formoterol was displaced to the left by PDE4, but not PDE3, inhibition. Overall, similar effects were described for bona fide genes, including RGS2, CD200, and CRISPLD2. Importantly, the combination of siguazodan plus rolipram prolonged the duration of gene expression induced by formoterol, dexamethasone, or dexamethasone plus formoterol. This was most apparent for RGS2, a bronchoprotective gene that may also reduce the proinflammatory effects of constrictor mediators. Collectively, these data provide a rationale for the use of PDE3 and PDE4 inhibitors in the treatment of COPD and asthma where they may enhance, sensitize, and prolong the effects of LABA/ICS combination therapies.

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“…Conversely, in human airways smooth muscle cells, the expression of regulator of G-protein signaling 2 (RGS2), a Ga q -selective GTPase-activating protein (Heximer, 2004;Kimple et al, 2009), is synergistically enhanced by glucocorticoid plus LABA . Because RGS2 attenuates responses from Ga q -linked G protein-coupled receptors (GPCRs), such as airway smooth muscle contraction Xie et al, 2012), we reasoned that relevant responses in other cells that express the b 2 -adrenoceptor, including airway epithelia, might be affected similarly.…”

Section: Introductionmentioning

confidence: 99%

Induction of Regulator of G-Protein Signaling 2 Expression by Long-Acting β₂-Adrenoceptor Agonists and Glucocorticoids in Human Airway Epithelial Cells

Holden

George

Rider

et al. 2013

J Pharmacol Exp Ther

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In asthma and chronic obstructive pulmonary disease (COPD) multiple mediators act on Ga q -linked G-protein-coupled receptors (GPCRs) to cause bronchoconstriction. However, acting on the airway epithelium, such mediators may also elicit inflammatory responses. In human bronchial epithelial BEAS-2B cells (bronchial epithelium 1 adenovirus 12-SV40 hybrid), regulator of G-protein signaling (RGS) 2 mRNA and protein were synergistically induced in response to combinations of long-acting b 2 -adrenoceptor agonist (LABA) (salmeterol, formoterol) plus glucocorticoid (dexamethasone, fluticasone propionate, budesonide). Equivalent responses occurred in primary human bronchial epithelial cells. Concentrations of glucocorticoid plus LABA required to induce RGS2 expression in BEAS-2B cells were consistent with the levels achieved therapeutically in the lungs. As RGS2 is a GTPase-activating protein that switches off Ga q , intracellular free calcium ([Ca 21 ] i ) flux was used as a surrogate of responses induced by histamine, methacholine, and the thromboxane receptor agonist U46619. This was significantly attenuated by salmeterol plus dexamethasone pretreatment, or RGS2 overexpression, and the protective effect of salmeterol plus dexamethasone was abolished by RGS2 RNA silencing. Although methacholine and U46619 induced interleukin-8 (IL-8) release and this was inhibited by RGS2 overexpression, the repression of U46619-induced IL-8 release by salmeterol plus dexamethasone was unaffected by RGS2 knockdown. Given a role for Ga q -mediated pathways in inducing IL-8 release, we propose that RGS2 acts redundantly with other effector processes to repress IL-8 expression. Thus, RGS2 expression is a novel effector mechanism in the airway epithelium that is induced by glucocorticoid/LABA combinations. This could contribute to the efficacy of glucocorticoid/LABA combinations in asthma and COPD.

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Regulator of G protein signaling 2 is a key modulator of airway hyperresponsiveness

Cited by 42 publications

References 48 publications

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Superiority of Combined Phosphodiesterase PDE3/PDE4 Inhibition over PDE4 Inhibition Alone on Glucocorticoid- and Long-Acting β₂-Adrenoceptor Agonist–Induced Gene Expression in Human Airway Epithelial Cells

Induction of Regulator of G-Protein Signaling 2 Expression by Long-Acting β₂-Adrenoceptor Agonists and Glucocorticoids in Human Airway Epithelial Cells

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Regulator of G protein signaling 2 is a key modulator of airway hyperresponsiveness

Cited by 42 publications

References 48 publications

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

Superiority of Combined Phosphodiesterase PDE3/PDE4 Inhibition over PDE4 Inhibition Alone on Glucocorticoid- and Long-Acting β2-Adrenoceptor Agonist–Induced Gene Expression in Human Airway Epithelial Cells

Induction of Regulator of G-Protein Signaling 2 Expression by Long-Acting β2-Adrenoceptor Agonists and Glucocorticoids in Human Airway Epithelial Cells

Contact Info

Product

Resources

About

Superiority of Combined Phosphodiesterase PDE3/PDE4 Inhibition over PDE4 Inhibition Alone on Glucocorticoid- and Long-Acting β₂-Adrenoceptor Agonist–Induced Gene Expression in Human Airway Epithelial Cells

Induction of Regulator of G-Protein Signaling 2 Expression by Long-Acting β₂-Adrenoceptor Agonists and Glucocorticoids in Human Airway Epithelial Cells