Muscarinic receptor-β-adrenoceptor cross-talk in airways smooth muscle

Elzinga, Carolina

doi:10.1007/978-3-0348-8358-0_6

Cited by 5 publications

(6 citation statements)

References 197 publications

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“…M 3 receptors crucially influence the function of these receptors by activation of protein kinase C (PKC) and direct phosphorylation of β 2 receptors, as well as G rms protein, promoting receptor decoupling with its G protein, as well as desensitization (Meurs et al, 2001); in addition to phosphorylation by a G-protein receptor kinase (GRK), the β-adrenoceptor kinase (BARK), amplifying the desensitization of these receptors (Boterman et al, 2006). Additionally, ACh acting via M 2 receptors counteracts the bronchodilator actions of β 2 agonists by reducing the cAMP levels due to inhibition of adenylate cyclase (AC) (Montuschi and Ciabattoni, 2015).…”

Section: Discussionmentioning

confidence: 99%

A Guinea Pig Model of Airway Smooth Muscle Hyperreactivity Induced by Chronic Allergic Lung Inflammation: Contribution of Epithelium and Oxidative Stress

Lhc

Mdcc

et al. 2019

Front. Pharmacol.

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Asthma is a heterogeneous disease of the airways characterized by chronic inflammation associated with bronchial and smooth muscle hyperresponsiveness. Currently, different murine models for the study of asthma show poor bronchial hyperresponsiveness due to a scarcity of smooth muscle and large airways, resulting in a failure to reproduce smooth muscle hyperreactivity. Thus, we aimed to standardize a guinea pig model of chronic allergic lung inflammation mimicking airway smooth muscle hyperreactivity observed in asthmatics (Asth). Animals were randomly divided into a control group (Ctrl), which received saline (0.9% NaCl), and the Asth group, subjected to in vivo sensitization with ovalbumin (OVA) nebulization. Morphological analysis was performed by hematoxylin-eosin staining. Bronchial hyperresponsiveness was evaluated by nebulization time in the fifth, sixth, and seventh inhalations (NT5-7) and tracheal isometric contractions were assessed by force transducer. Total antioxidant capacity was measured by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method and protein expression by Western blot. Histologically, the Asth group developed peribronchial cellular infiltrate, epithelial hyperplasia and smooth muscle thickening. After the fourth nebulization, the Asth group developed bronchial hyperreactivity. The trachea from the Asth group contracted after in vitro stimulation with OVA, differing from the Ctrl group, which showed no response. Additionally, airway smooth muscle hyperreactivity to carbachol and histamine was observed in the Asth group only in intact epithelium preparations, but not to KCl, and this effect was associated with an augmented production of reactive oxygen species. Moreover, lung inflammation impaired the relaxant potency of isoproterenol only in intact epithelium preparations, without interfering with nifedipine, and it was found to be produced by transforming growth factor-β negative modulation of β adrenergic receptors and, furthermore, big-conductance Ca 2+ -sensitive K + channels. These effects were also associated with increased levels of phosphatidylinositol 3-kinases but not extracellular signal-regulated kinases 1/2 or phosphorylation, and augmented α-actin content as well, explaining the increased smooth muscle mass. Furthermore, pulmonary antioxidant capacity was impaired in the Asth group. Therefore, we developed a standardized and easy-to-use, reproducible guinea pig model of lung inflammation that mimics airway smooth muscle hypercontractility, facilitating the investigation of the mechanisms of bronchial hyperresponsiveness in asthma and new therapeutic alternatives.

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Section: Discussionmentioning

confidence: 99%

A Guinea Pig Model of Airway Smooth Muscle Hyperreactivity Induced by Chronic Allergic Lung Inflammation: Contribution of Epithelium and Oxidative Stress

Lhc

Mdcc

et al. 2019

Front. Pharmacol.

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“…DAG triggers the translocation and activation of protein kinase C, which is able to phosphorylate a variety of protein substrates [164]. Cross-talk between G i -coupled M 2 receptors and G s -protein (G s )-coupled b-adrenoceptors (having opposing effects on cyclic AMP accumulation) has no major effects on modulation of muscarinic-agonist-induced contraction or b-agonist-induced relaxation, at least under physiological conditions [165]. In contrast, G q -coupled M 3 receptors may have a major influence on b-adrenoceptor function, even in noninflamed airways.…”

Section: Cholinergic Mechanismsmentioning

confidence: 99%

“…In contrast, G q -coupled M 3 receptors may have a major influence on b-adrenoceptor function, even in noninflamed airways. This is due to DAG-induced activation of protein kinase C, which may: 1) phosphorylate the b 2 -adrenoceptor, as well as Gs, causing receptor uncoupling and desensitisation [165]; and 2) phosphorylate and activate b-adrenoceptor kinases, which are members of the G-protein-coupled receptor kinase family, amplifying homologous b-agonist induced desensitisation [166,167]. These processes may explain the well-known attenuation of b-agonist efficacy during episodes of severe bronchoconstriction, for example during exacerbations.…”

Section: Cholinergic Mechanismsmentioning

confidence: 99%

Airway hyperresponsiveness in asthma: lessons fromin vitromodel systems and animal models: Fig. 1—

Gosens¹,

Zaagsma²

2008

Eur Respir J

107

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Airway hyperresponsiveness (AHR) is a hallmark clinical symptom of asthma. At least two components of AHR have been identified: 1) baseline AHR, which is persistent and presumably caused by airway remodelling due to chronic recurrent airway inflammation; and 2) acute and variable AHR, which is associated with an episodic increase in airway inflammation due to environmental factors such as allergen exposure.Despite intensive research, the mechanisms underlying acute and chronic AHR are poorly understood. Owing to the complex variety of interactive processes that may be involved, in vitro model systems and animal models are indispensable to the unravelling of these mechanisms at the cellular and molecular level.The present paper focuses on a number of translational studies addressing the emerging central role of the airway smooth muscle cell, as a multicompetent cell involved in acute airway constriction as well as structural changes in the airways, in the pathophysiology of airway hyperresponsiveness.

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“…Thus, studies in human (Raffestin et al, 1985;Van Amsterdam et al, 1990) and animal (Torphy et al, 1985;Van Amsterdam et al, 1989b) airway smooth muscle preparations have demonstrated that the potency and efficacy of b 2 -agonists are gradually reduced in the presence of increasing concentrations of contractile stimuli, including muscarinic receptor agonists and histamine. The reduced b-adrenergic responsiveness may importantly be attributed to cross-talk between G q -coupled muscarinic M 3 -or histamine H 1 -receptors and G s -coupled b 2 -adrenoceptors (Van Amsterdam et al, 1989b, 1990Grandordy et al, 1994;Meurs et al, 2001), presumably via protein kinase C-induced phosphorylation of the b 2 -adrenoceptor and/or G s (Sibley and Lefkowitz, 1985;Pyne et al, 1992a,b;Boterman et al, 2005). In addition, it has been demonstrated that protein kinase C activation enhances b-agonist-induced b 2 -adrenoceptor desensitization in airway smooth muscle (Boterman et al, 2006), which could involve phosphorylation and activation of G-protein-coupled receptor kinase 2 (Chuang et al, 1995(Chuang et al, , 1996.…”

Section: Introductionmentioning

confidence: 99%

Bronchoprotection by Olodaterol Is Synergistically Enhanced by Tiotropium in a Guinea Pig Model of Allergic Asthma

Smit

Zuidhof

Bos

et al. 2013

J Pharmacol Exp Ther

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The novel once-daily b 2 -agonist bronchodilator drug olodaterol has recently been shown to be effective in patients with allergic asthma for .24 hours. An increased cholinergic tone common to these patients may decrease the effectiveness of b 2 -agonists. This could provide a rationale for combination therapy with olodaterol and the long-acting anticholinergic tiotropium to aim for a once-daily treatment regimen. In guinea pigs, we evaluated the protective effects of olodaterol, alone and in combination with tiotropium, on airway responsiveness to histamine, which is partially mediated by a cholinergic reflex mechanism. In addition, using a guinea pig model of acute allergic asthma, we examined the cooperative effects of these bronchodilators on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyper-responsiveness (AHR) to histamine, and airway inflammation. It was demonstrated that the protective effect of olodaterol against histamine-induced bronchoconstriction was synergistically enhanced and prolonged in the presence of tiotropium. In addition, tiotropium synergistically augmented both the reversal of and the protection against the allergeninduced AHR after the EAR by olodaterol. Olodaterol and tiotropium were highly effective in inhibiting the magnitude of the allergen-induced EAR and LAR, and both reactions were fully inhibited by the combination of these drugs. It is remarkable that these effects were not associated with an effect on inflammatory cell infiltration in the airways. In conclusion, the results indicate that combination therapy with olodaterol and tiotropium may be highly effective in the treatment of allergen-induced asthmatic reactions and AHR.

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Muscarinic receptor-β-adrenoceptor cross-talk in airways smooth muscle

Cited by 5 publications

References 197 publications

A Guinea Pig Model of Airway Smooth Muscle Hyperreactivity Induced by Chronic Allergic Lung Inflammation: Contribution of Epithelium and Oxidative Stress

A Guinea Pig Model of Airway Smooth Muscle Hyperreactivity Induced by Chronic Allergic Lung Inflammation: Contribution of Epithelium and Oxidative Stress

Airway hyperresponsiveness in asthma: lessons fromin vitromodel systems and animal models: Fig. 1—

Bronchoprotection by Olodaterol Is Synergistically Enhanced by Tiotropium in a Guinea Pig Model of Allergic Asthma

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