Salmeterol and cytokines modulate inositol-phosphate signalling in Human airway smooth muscle cells via regulation at the receptor locus

Smith, Natalie E.; Browning, Claudia A.; Duroudier, Nathalie P.; Stewart, Ceri E.; Peel, Samantha; Swan, Caroline; Hall, Ian P.; Sayers, Ian

doi:10.1186/1465-9921-8-68

Cited by 7 publications

(8 citation statements)

References 46 publications

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“…Primary human airway smooth muscle (HASM) cells were isolated and prepared as described previously [ 39 ] and cultured in DMEM + 10% foetal calf serum (FCS). Airway smooth muscle cells from two individuals were used.…”

Section: Methodsmentioning

confidence: 99%

“…Transcription factors relevant to respiratory disease and asthma were identified by reference to the literature (AP1, NFKB, NF-AT, CREB, STAT, C/EBP, GR, RXR, SRC-1, TIF-2, p/CAF, CBP, GATA)[ 41 , 42 ]. A 4000 bp fragment upstream of the transcriptional start site was analysed for potential transcription factor binding sites using four different algorithms available online, as described previously [ 39 ]. Results of these searches were compared and those binding sites identified in two or more different searches were included in a final summary.…”

Section: Methodsmentioning

confidence: 99%

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Characterisation of urokinase plasminogen activator receptor variants in human airway and peripheral cells

Stewart

Sayers

2009

BMC Mol Biol

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Background: Expression of the urokinase plasminogen activator receptor (UPAR) has been shown to have clinical relevance in various cancers. We have recently identified UPAR as an asthma susceptibility gene and there is evidence to suggest that uPAR may be upregulated in lung diseases such as COPD and asthma. uPAR is a key receptor involved in the formation of the serine protease plasmin by interacting with uPA and has been implicated in many physiological processes including proliferation and migration. The current aim was to determine key regulatory regions and splice variants of UPAR and quantify its expression in primary human tissues and cells (including lung, bronchial epithelium (HBEC), airway smooth muscle (HASM) and peripheral cells).

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Characterisation of urokinase plasminogen activator receptor variants in human airway and peripheral cells

Stewart

Sayers

2009

BMC Mol Biol

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“…The potential mechanisms underlying these observations are complex and are not fully understood, but recent evidence (30,32) suggests that prolonged exposure of human ASM cells to these drugs in vitro can augment spasmogen-mediated inositol phosphate production and thereby potentially exacerbate contractile tone in the airway. Although we did not study the effect that endogenous GABA A activation may confer in a model of prolonged ␤ 2 -adrenoceptor agonist exposure, the facilitation of relaxation achieved by cotreatment (GABA A agonist and ␤ 2 -adrenoceptor agonist) may provide better symptomatic relief at lower doses of ␤-agonists and theoretically could reduce the amount of ␤ 2 -adrenoceptor agonist required for chronic maintenance therapy.…”

Section: Discussionmentioning

confidence: 99%

Activation of endogenous GABA_A channels on airway smooth muscle potentiates isoproterenol-mediated relaxation

Gallos¹,

Gleason²,

Zhang³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Emala CW. Activation of endogenous GABAA channels on airway smooth muscle potentiates isoproterenol-mediated relaxation. Am J Physiol Lung Cell Mol Physiol 295: L1040 -L1047, 2008. First published September 12, 2008 doi:10.1152/ajplung.90330.2008.-Reactive airway disease predisposes patients to episodes of acute smooth muscle mediated bronchoconstriction. We have for the first time recently demonstrated the expression and function of endogenous ionotropic GABAA channels on airway smooth muscle cells. We questioned whether endogenous GABAA channels on airway smooth muscle could augment ␤-agonist-mediated relaxation. Guinea pig tracheal rings or human bronchial airway smooth muscles were equilibrated in organ baths with continuous digital tension recordings. After pretreatment with or without the selective GABAA antagonist gabazine (100 M), airway muscle was contracted with acetylcholine or ␤-ala neurokinin A, followed by relaxation induced by cumulatively increasing concentrations of isoproterenol (1 nM to 1 M) in the absence or presence of the selective GABAA agonist muscimol (10 -100 M). In separate experiments, guinea pig tracheal rings were pretreated with the large conductance KCa channel blocker iberiotoxin (100 nM) after an EC50 contraction with acetylcholine but before cumulatively increasing concentrations of isoproterenol (1 nM to 1 uM) in the absence or presence of muscimol (100 uM). GABAA activation potentiated the relaxant effects of isoproterenol after an acetylcholine or tachykinin-induced contraction in guinea pig tracheal rings or an acetylcholine-induced contraction in human endobronchial smooth muscle. This muscimol-induced potentiation of relaxation was abolished by gabazine pretreatment but persisted after blockade of the maxi KCa channel. Selective activation of endogenous GABAA receptors significantly augments ␤-agonist-mediated relaxation of guinea pig and human airway smooth muscle, which may have important therapeutic implications for patients in severe bronchospasm. guinea pig; organ bath; gabazine; muscimol ASTHMA IS A CHRONIC inflammatory disease of the airways the prevalence of which both in the United States and throughout much of the world has taken on pandemic proportions (4). Standard treatment for asthma centers on pharmacological attenuation of hyperresponsiveness either by modulation of inflammatory mediators or by promoting airway smooth muscle (ASM) relaxation (e.g., ␤ 2 -adrenoceptor agonists). Although research over the past three decades has made great strides in elucidating many of the underlying mechanisms involved in this disease, few novel additions to the pharmacological armamentarium have occurred in the treatment of reactive airway disease.␤ 2 -Adrenoceptor agonists retain a prominent role in the clinical treatment of airway hyperresponsiveness, and the mechanisms by which ␤ 2 -adrenoceptor agonists relax ASM include both cAMP-dependent and cAMP-independent pathways. Additionally, regulation of ␤ 2 -adrenoceptor activity either through desensitization or downregu...

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“…When PI production is specifically assessed, different routes of G αq -mediated stimulation impart different outcomes with histamine- but not methacholine-induced PI production inhibited by elevators of cAMP [38, 39]. Conversely, in human cultured ASM cells, a small increase in histamine-induced PI hydrolysis was reported following exposure to salmeterol potentially reflecting the somewhat modified ASM phenotype observed following repeated cell culture [40]. …”

Section: Mechanisms Of β2ar-mediated Asm Relaxationmentioning

confidence: 99%

cAMP regulation of airway smooth muscle function

Billington¹,

Ojo²,

Penn³

et al. 2013

Pulmonary Pharmacology & Therapeutics

182

144

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Agonists activating β2-adrenoceptors (β2ARs) on airway smooth muscle (ASM) are the drug of choice for rescue from acute bronchoconstriction in patients with both asthma and chronic obstructive pulmonary disease (COPD). Moreover, the use of long-acting β-agonists combined with inhaled corticosteroids constitutes an important maintenance therapy for these diseases. β-Agonists are effective bronchodilators due primarily to their ability to antagonize ASM contraction. The presumed cellular mechanism of action involves the generation of intracellular cAMP, which in turn can activate the effector molecules cAMP-dependent protein kinase (PKA) and Epac. Other agents such as prostaglandin E2 and phosphodiesterase inhibitors that also increase intracellular cAMP levels in ASM, can also antagonize ASM contraction, and inhibit other ASM functions including proliferation and migration. Therefore, β2ARs and cAMP are key players in combating the pathophysiology of airway narrowing and remodeling. However, limitations of β-agonist therapy due to drug tachyphylaxis related to β2AR desensitization, and recent findings regarding the manner in which β2ARs and cAMP signal, have raised new and interesting questions about these well-studied molecules. In this review we discuss current concepts regarding β2ARs and cAMP in the regulation of ASM cell functions and their therapeutic roles in asthma and COPD.

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Salmeterol and cytokines modulate inositol-phosphate signalling in Human airway smooth muscle cells via regulation at the receptor locus

Cited by 7 publications

References 46 publications

Characterisation of urokinase plasminogen activator receptor variants in human airway and peripheral cells

Characterisation of urokinase plasminogen activator receptor variants in human airway and peripheral cells

Activation of endogenous GABA_A channels on airway smooth muscle potentiates isoproterenol-mediated relaxation

cAMP regulation of airway smooth muscle function

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