β2-Agonist Induced cAMP Is Decreased in Asthmatic Airway Smooth Muscle Due to Increased PDE4D

Trian, Thomas; Burgess, Janette K.; Niimi, Kyoko; Moir, Lyn M.; Ge, Qi; Berger, Patrick; Liggett, Stephen B.; Black, Judith L.; Oliver, Brian G.

doi:10.1371/journal.pone.0020000

Cited by 81 publications

(70 citation statements)

References 34 publications

(62 reference statements)

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“…Such alterations have been observed in vivo and ex vivo in human and animal airways and in cultured HASM cells (14)(15)(16)(17)(18)(19)(20). These findings include altered [Ca 21 ] signaling from G q -coupled receptors, such as M 3 -muscarinic and H1-histamine, and cAMP signaling from b 2 AR (14,17,18). Given that some of these signaling effects are found in passaged cultured HASM cells, in the absence of the inflammatory airway milieu, asthmatic HASM may be "hardwired" by genetic or epigenetic mechanisms to be procontractile and/or resistant to relaxation.…”

Section: Clinical Relevancementioning

confidence: 87%

“…The asthmatic state has long been recognized as one that includes dysregulation of airway GPCRs, including those that act to contract and relax airway smooth muscle. Such alterations have been observed in vivo and ex vivo in human and animal airways and in cultured HASM cells (14)(15)(16)(17)(18)(19)(20). These findings include altered [Ca 21 ] signaling from G q -coupled receptors, such as M 3 -muscarinic and H1-histamine, and cAMP signaling from b 2 AR (14,17,18).…”

Section: Clinical Relevancementioning

confidence: 93%

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Bitter Taste Receptor Function in Asthmatic and Nonasthmatic Human Airway Smooth Muscle Cells

Robinett

Koziol‐White

Akoluk

et al. 2014

Am J Respir Cell Mol Biol

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Bitter taste receptors (TAS2Rs) have recently been found to be expressed on human airway smooth muscle (HASM), and their activation results in marked relaxation. These agents have been proposed as a new class of bronchodilators in the treatment of obstructive lung diseases because they act via a different mechanism than b-agonists. The TAS2R signal transduction pathway in HASM has multiple elements that are potentially subject to regulation by inflammatory, genetic, and epigenetic mechanisms associated with asthma. To address this, expression, signaling, and physiologic functions of the three major TAS2Rs (subtypes 10, 14, and 31) on HASM were studied. Transcript expression of these TAS2Rs was not decreased in HASM cells derived from donors with asthma compared with those without asthma (n = 6 from each group). In addition, intracellular calcium ([Ca 21 ] i ) signaling using TAS2R subtype-specific agonists (diphenhydramine, chloroquine, saccharin, and flufenamic acid) was not impaired in the cells derived from donors with asthma, nor was the response to quinine, which activates all three subtypes. HASM cell mechanics measured by magnetic twisting cytometry revealed equivalent TAS2R-mediated relaxation of methacholine-treated cells between the two groups. Human precision-cut lung slices treated with IL-13 caused a decrease in b-agonist (formoterol)-mediated relaxation of carbacholcontracted airways compared with control slices. In contrast, TAS2R-mediated relaxation was unaffected by IL-13. We conclude that TAS2R expression or function is unaffected in HASM cells derived from patients with asthma or the IL-13 inflammatory environment.

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Section: Clinical Relevancementioning

confidence: 87%

Section: Clinical Relevancementioning

confidence: 93%

Bitter Taste Receptor Function in Asthmatic and Nonasthmatic Human Airway Smooth Muscle Cells

Robinett

Koziol‐White

Akoluk

et al. 2014

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

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“…It can stimulate adenylyl cyclase and subsequently generate an important regulatory second messenger, cAMP. In turn, increased levels of cAMP can stimulate cAMP-dependent protein kinase A. Calcium extrusion and sequestration is then induced and thus results in smooth muscle relaxation (16,17). Therefore, the mechanism of drug action can be preliminarily understood by detecting the influence of the tested drugs on the cAMP content, and determining the intensity of the airway expansion from a deeper lever.…”

Section: Discussionmentioning

confidence: 99%

Stereoselective activity of 2-(4-amino-3-chloro-5- trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride to improve the pulmonary function in asthma

Pan

et al. 2014

Biomedical Reports

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Abstract. Asthma is a chronic airway disease that is characterized by significantly exacerbated bronchospasms and marked inflammation of the airways. Although the etiology of asthma remains to be determined, genetic predisposition is one of the factors involved. β 2 -agonists compounds may serve as options for the treatment of bronchial asthma. The aim of the present study was to investigate the effects of 2-(4-amino-3-chloro-5-t rifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride (SPFF) and its enantiomers with regard to improving asthmatic pulmonary function and selective binding to β 2 -adrenergic receptor. The bronchoconstrictor action of histamine in guinea pigs was conducted and the results demonstrated that (-)SPFF and (±)SPFF could significantly inhibit the increase of bronchoconstriction induced by histamine, while (+)SPFF did not show an effect. Inflammatory mediator release from allergic lung tissues was determined and it was found that (±)SPFF showed the highest activity among all the tested compounds, while the efficacy of (-)SPFF was similar to that of (+)SPFF. SPFF and its enantiomers stimulated cyclic adenosine monophosphate (cAMP) production in the asthmatic lung tissues examined, showing that asthmatic lung tissues had a significant cAMP enhancement in response to (-)SPFF and (±)SPFF compared with (+)SPFF. Cardiac contractility of the right atria was assessed in the guinea pigs to establish the receptor selectivity of the compounds. The results indicated that all the compounds had high affinities to the β 2 receptor. In conclusion, with regards to asthmatic pulmonary function improvement, (-)SPFF was more efficient as compared to (+) SPFF, while no significant difference was observed for the receptor selectivity of (-)SPFF and (+)SPFF.

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“…PDE4 is shown to be the major PDE subtype in human ASM cells (36). It hydrolyzes cAMP, which is known to activate protein kinase A (PKA)-and exchange protein directly activated by cAMP (Epac)-dependent pathways to regulate ASM functions, such as inhibition of ASM cell proliferation and airway constriction (37)(38)(39). The dramatic increase in pde4 d expression in lungs of HDM-challenged mice, therefore, could cause a significant reduction in cAMP and enhance airway reactivity and remodeling.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Alterations by DNA Methylation in House Dust Mite–Induced Airway Hyperresponsiveness

Shang

Das

Rabold

et al. 2013

Am J Respir Cell Mol Biol

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Asthma is one of the most prevalent chronic lung diseases, affecting 235 million individuals around the world, with its related morbidity and mortality increasing steadily over the last 20 years. Exposure to the environmental allergen, house dust mite (HDM), results in airway inflammation with a variable degree of airway obstruction. Although there has been much experimental work in the past using HDM challenge models to understand mechanistic details in allergic inflammation and airway hyperresponsiveness (AHR), there has been no study on reprogramming of lung or airways mediated through epigenetic mechanisms in response to an acute HDM exposure. Male mice, 6 weeks of age, were administrated HDM extracts or saline at Days 1, 14, and 21. Exposure of mice to HDM extracts caused significant airway inflammation and increased AHR. These HDMchallenged mice also exhibited a change in global DNA methylation as compared with saline-exposed (control) mice. Next, by employing methylation-sensitive restriction fingerprinting, we identified a set of genes, showing aberrant methylation status, associated with the HDM-induced AHR. These candidate genes are known to be involved in cAMP signaling (pde4 d), Akt-signaling (akt1 s1), ion transport (tm6 sf1, pom121l2, and slc8a3), and fatty acid metabolism (acsl3). Slc8a3 and acsl3 were down-regulated, whereas pde4 d, akt1 s1, tm6 sf1, and pom121l2 were up-regulated in the mice exposed to HDM. Hence, our results suggest that HDM exposure induces a series of aberrant methylated genes that are potentially important for the development of allergic AHR.Keywords: airway hyperresponsiveness; DNA methylation; epigenetics; house dust mite Asthma is one of the most prevalent chronic lung diseases, affecting 235 million individuals around the world (www.who.int). Individuals with asthma experience great difficulties in breathing and have reduced quality of life, with repeated visits to clinics or emergency rooms. It is well recognized that the development of asthma is related to a combination of genetic and environmental factors, but the precise mechanisms of pathogenesis in asthma are still unclear (1, 2). There are many triggers of asthmatic attacks; most of them are associated with environmental exposure to allergens. In the inner city environment, house dust mite (HDM) allergy is reported to be the most prevalent cause of allergic sensitization in individuals with asthma (3). Exposure to HDM results in airway inflammation with a variable degree of airway obstruction. In animal studies, chronic exposure of mice to HDM leads to significant airway inflammation, increased airway hyperresponsiveness (AHR), and remodeling of bronchi (4-6). Even though much work has been done in the past using this HDM model to probe the immunologic pathways, there is no study addressing the epigenetic basis of how this environmental allergen "reprograms" the airways, thereby predisposing the animals to asthma.Epigenetics provide a promising approach for improving our understanding of complex diseases like asth...

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β2-Agonist Induced cAMP Is Decreased in Asthmatic Airway Smooth Muscle Due to Increased PDE4D

Cited by 81 publications

References 34 publications

Bitter Taste Receptor Function in Asthmatic and Nonasthmatic Human Airway Smooth Muscle Cells

Bitter Taste Receptor Function in Asthmatic and Nonasthmatic Human Airway Smooth Muscle Cells

Stereoselective activity of 2-(4-amino-3-chloro-5- trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride to improve the pulmonary function in asthma

Epigenetic Alterations by DNA Methylation in House Dust Mite–Induced Airway Hyperresponsiveness

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