Steroids completely reverse albuterol-induced β2-adrenergic receptor tolerance in human small airways

Cooper, Philip; Panettieri, Reynold A.

doi:10.1016/j.jaci.2008.07.040

Cited by 101 publications

(104 citation statements)

References 18 publications

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“…One explanation of this could be a reduction of agonist tolerance associated with ICS use, as suggested by experimental data [4]. Airway smooth muscle tone is controlled by guanosine triphosphate-binding protein (G s )a-(i.e.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that genetically mediated paradoxical bronchial obstruction or hyperresponsiveness may occur with long-term use of b-agonists [22]. Steroids have shown in experimental in vitro and in vivo studies to reverse functional desensitisation of b 2 -AR [4,23,24], increase receptor expression and density, and enhance expression of G s a, producing a dose-dependent increase in cyclic adenosine monophosphate levels [25,26]. However, in humans, loss of bronchoprotection from regularly administered b 2 -agonists seems to reverse only with acute high doses of ICS [27,28] and it is not clear that this happens with chronic use of ICS at low or medium doses [29][30][31].…”

Section: Discussionmentioning

confidence: 99%

“…In vitro studies have shown that the nonsynonymous single-nucleotide polymorphism at position 46 (rs1042713; herein referred to as Gly16Arg) in the ADRB2 gene shows an enhanced agonist-promoted downregulation [3]. In vitro studies evaluating concomitant use of steroids and b 2 -agonists also suggest that inhaled corticosteroids (ICSs) may counteract b 2 -AR desensitisation [4]. In vivo evidence suggests the presence of a differential response to short-acting b 2 -agonist (SABA) treatment according to ADRB2 Gly16Arg genotype [5].…”

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confidence: 99%

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ADRB2Gly16Arg polymorphism, asthma control and lung function decline

Rebordosa¹,

Kogevinas

Guerra

et al. 2011

Eur Respir J

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Arg/Arg homozygotes for the Gly16Arg polymorphism in the b 2 -adrenoreceptor gene (ADRB2) have a reduced response to short-acting b 2 -agonists but no effect has been associated with long-acting b 2 -agonists (LABAs).We selected 604 subjects with current asthma from the European Community Respiratory Health Study to evaluate whether asthma control and lung function decline were associated with Gly16Arg polymorphism, and to test whether LABA or inhaled corticosteroid (ICS) use modified these effects.There was an increased risk of noncontrolled asthma (OR 1.33, 95% CI 1.01-1.75; p50.046) for each Arg allele. Among nonusers of ICS, the odds ratio of noncontrolled asthma among Arg/Arg versus Gly/Gly subjects was 2.73 (95% CI 1.28-5.82; p50.009). No increased risk of noncontrolled asthma associated with the Arg allele was observed among ICS and/or LABA users. For each Arg allele, a mean¡SE decrease in decline in forced expiratory volume in 1 s of 7.7¡2.5 mL?yr -1 was found (p-value for trend 0.003), irrespective of ICS or LABA use. Arg/Arg subjects had an increased risk of bronchial hyperresponsiveness (BHR) versus Gly/Gly subjects, with an odds ratio of 2.51 (95% CI 1.12-5.63; p50.025) if they did not use ICS. The Arg allele was associated with poorer asthma control, a steeper lung function decline and BHR. Absence of genotypic effects on asthma control among ICS users may be due to reversed b 2 -adrenoreceptor desensitisation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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ADRB2Gly16Arg polymorphism, asthma control and lung function decline

Rebordosa¹,

Kogevinas

Guerra

et al. 2011

Eur Respir J

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“…Cell Culture-Human ASM cells were isolated from lung transplant donors as previously described in accordance with procedures approved by the University of Pennsylvania Committee on Studies Involving Human Beings (11). The cells were routinely maintained in Ham's F-12 medium (Invitrogen) supplemented with 10% fetal bovine serum, 100 units/ml penicillin, 100 g/ml streptomycin, and 25 mM HEPES buffer.…”

Section: Methodsmentioning

confidence: 99%

“…We used a dexamethasone concentration previously shown to prevent ␤ 2 -agonist desensitization in PCLS without affecting growth factor-induced ASM proliferation (11,36). RGS5 expression was reduced in salbutamol-treated cells compared with control (Fig.…”

Section: ␤-Agonist Regulation Of Bronchial Rgs5 Expressionmentioning

confidence: 99%

β-Agonist-associated Reduction in RGS5 Expression Promotes Airway Smooth Muscle Hyper-responsiveness

Yang

Cooper

Damera

et al. 2011

Journal of Biological Chemistry

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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 -agonistinduced 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 agonistevoked 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.Asthma is a complex disorder of unknown etiology characterized by increased bronchial smooth muscle contraction, lung inflammation, and tissue remodeling. These and other abnormalities reduce airway luminal diameter and increase stiffness. A cardinal feature of asthma is "airway hyper-responsiveness" (AHR), 2 which refers to the increased bronchial contraction to inhaled procontractile agonists such as methacholine that is observed in asthmatics relative to healthy controls. AHR manifests as reduced airflow (1-4). In allergic asthma, mediators secreted by activated inflammatory leukocytes or resident lung cells including histamine, leukotrienes, bradykinin, and thrombin promote ASM contraction by activating GPCRs linked to activation (GTP binding) of G␣ q (5). This initiates a signaling route culminating in generation of inositol (3, 4, 5)-trisphosphate and release of Ca 2ϩ from endoplasmic reticulum by activation of IP3 receptors. Hydrolysis of GTP by G␣ q promotes pathway deactivation through formation of inactive G␣ q -GDP-G␤␥ heterotrimers. G␣ q signaling is required for AHR in mouse models of allergic airway inflammation (6).Receptor-related events increase the frequency of intracellular Ca 2ϩ oscillations in ASM, which induces Ca 2ϩ -calmodulindependent protein kinase (CaMK)-mediated activation of myosin light chain kinase (MLCK). Phosphorylation of myosin light chain (MLC) on Ser-19 by MLCK promotes actin-myosin filament interactions and muscle fiber shortening through the...

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Microphysiological Models of Lung Epithelium‐Alveolar Macrophage Co‐Cultures to Study Chronic Lung Disease

Lagowala,

Wally,

Wilmsen

et al. 2023

Advanced Biology

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The interactions between immune cells and epithelial cells influence the progression of many respiratory diseases, such as chronic obstructive pulmonary disease (COPD). In vitro models allow for the examination of cells in controlled environments. However, these models lack the complex 3D architecture and vast multicellular interactions between the lung resident cells and infiltrating immune cells that can mediate cellular response to insults. In this study, three complementary microphysiological systems are presented to delineate the effects of cigarette smoke and respiratory disease on the lung epithelium. First, the Transwell system allows the co‐culture of pulmonary immune and epithelial cells to evaluate cellular and monolayer phenotypic changes in response to cigarette smoke exposure. Next, the human and mouse precision‐cut lung slices system provides a physiologically relevant model to study the effects of chronic insults like cigarette smoke with the dissection of specific interaction of immune cell subtypes within the structurally complex tissue environment. Finally, the lung‐on‐a‐chip model provides an adaptable system for live imaging of polarized epithelial tissues that mimic the in vivo environment of the airways. Using a combination of these models, a complementary approach is provided to better address the intricate mechanisms of lung disease.

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Steroids completely reverse albuterol-induced β2-adrenergic receptor tolerance in human small airways

Cited by 101 publications

References 18 publications

ADRB2Gly16Arg polymorphism, asthma control and lung function decline

ADRB2Gly16Arg polymorphism, asthma control and lung function decline

β-Agonist-associated Reduction in RGS5 Expression Promotes Airway Smooth Muscle Hyper-responsiveness

Microphysiological Models of Lung Epithelium‐Alveolar Macrophage Co‐Cultures to Study Chronic Lung Disease

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