Concurrent Agonism of Adenosine A2B and Glucocorticoid Receptors in Human Airway Epithelial Cells Cooperatively Induces Genes with Anti-Inflammatory Potential: A Novel Approach to Treat Chronic Obstructive Pulmonary Disease

@article{Greer2013ConcurrentAO,
  title={Concurrent Agonism of Adenosine A2B and Glucocorticoid Receptors in Human Airway Epithelial Cells Cooperatively Induces Genes with Anti-Inflammatory Potential: A Novel Approach to Treat Chronic Obstructive Pulmonary Disease},
  author={Stephanie U. Greer and Cara Page and Taruna Joshi and Dong Yan and Robert Newton and Mark A. Giembycz},
  journal={The Journal of Pharmacology and Experimental Therapeutics},
  year={2013},
  volume={346},
  pages={473 - 485}
}
Chronic obstructive pulmonary disease (COPD) is a neutrophilic inflammatory disorder that is weakly responsive to glucocorticoids. Identification of ways to enhance the anti-inflammatory activity of glucocorticoids is, therefore, a major research objective. Adenosine receptor agonists that target the A2B-receptor subtype are efficacious in several cell-based assays and preclinical models of inflammation. Accordingly, the present study was designed to determine if a selective A2B-receptor… 
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References

SHOWING 1-10 OF 83 REFERENCES

A2B Adenosine Receptors Induce IL-19 from Bronchial Epithelial Cells, Resulting in TNF-α Increase

5′-(N-ethylcarboxamido)-adenosine (NECA), a stable analog of adenosine, increased the release of IL-19 by 4.6- ± 1.1-fold and a selective antagonist of the A2B receptor, CVT-6694, attenuated this effect of NECA.

Phosphodiesterase 4 Inhibitors Augment the Ability of Formoterol to Enhance Glucocorticoid-Dependent Gene Transcription in Human Airway Epithelial Cells: A Novel Mechanism for the Clinical Efficacy of Roflumilast in Severe Chronic Obstructive Pulmonary Disease

The ability of roflumilast and formoterol to interact in this way supports the concept that these drugs together may impart clinical benefit beyond that achievable by an ICS alone, a PDE4 inhibitor alone, or an I CS/LABA combination therapy.

β2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids

RGS2 gene expression is identified as a genomic mechanism of bronchoprotection that is induced by glucocorticoids plus LABAs in human airway smooth muscle and provide a rational explanation for the clinical efficacy of inhaled corticosteroid/LABA combinations in obstructive airways diseases.

A2B Adenosine Receptors Increase Cytokine Release by Bronchial Smooth Muscle Cells

The effect of Ado and its receptor subtypes on cytokine release by bronchial smooth muscle cells was determined using a cDNA array consisting of 23 cytokine genes and confirmed using real-time reverse transcription–polymerase chain reaction and enzyme-linked immunosorbent assay.

Long-Acting β2-Adrenoceptor Agonists Synergistically Enhance Glucocorticoid-Dependent Transcription in Human Airway Epithelial and Smooth Muscle Cells

It is proposed that enhancement of glucocorticoid-inducible gene expression may contribute to the superior efficacy of LABA/ICS combination therapies, over ICS alone, in asthma treatment.

Adora2b Adenosine Receptor Engagement Enhances Regulatory T Cell Abundance during Endotoxin-Induced Pulmonary Inflammation

Data indicate that the Adora2b adenosine receptor serves a potent anti-inflammatory role, functioning at least in part through the enhancement of Tregs, to limit inflammation.

Pharmacological strategies for improving the efficacy and therapeutic ratio of glucocorticoids in inflammatory lung diseases.

A2B adenosine receptors regulate the mucus clearance component of the lung's innate defense system.

The goal was to determine which ADO receptor (ADO-R) underlies ASL volume regulation in bronchial epithelia and to suggest that the cell surface may be in excess of 1 microM, which is sufficient to activate A(2B)-R.

The anti-inflammatory effect of glucocorticoids is mediated by glucocorticoid-induced leucine zipper in epithelial cells.

Adenosine receptors and inflammation.

The potent effects of adenosine signaling on the regulation of inflammation suggest that targeting specificadenosine receptor activation or inactivation using selective agonists and antagonists could have important therapeutic implications in numerous diseases.
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