Molecular mechanisms of combination therapy with inhaled corticosteroids and long-acting β-agonists

Black, JL; Oliver, BGG; Roth, M

Molecular mechanisms of combination therapy with inhaled corticosteroids and long-acting β-agonists

Black, JL Oliver, BGG

Roth, M

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Publication Type:: Journal Article
Citation:: Chest, 2009, 136 (4), pp. 1095 - 1100
Issue Date:: 2009-10-01

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Field	Value	Language
dc.contributor.author	Black, JL	en_US
dc.contributor.author	Oliver, BGG https://orcid.org/0000-0002-7122-9262	en_US
dc.contributor.author	Roth, M	en_US
dc.date.issued	2009-10-01	en_US
dc.identifier.citation	Chest, 2009, 136 (4), pp. 1095 - 1100	en_US
dc.identifier.issn	0012-3692	en_US
dc.identifier.uri	http://hdl.handle.net/10453/30745
dc.description.abstract	The treatment of asthma relies on the use of the following two major drug classes: β2-agonists, both short acting and long acting; and corticosteroids (CSs). Although the properties of each drug class are well described, their use in combination delivered either separately or through one device has provided some clear and important clinical advantages. The mechanisms underlying these interactions have emerged as novel and provocative. β2-Agonists can stimulate the glucocorticoid receptor (GR) and promote its translocation to the nucleus, resulting in increased CS-mediated gene transcription. In structural airway cells, such as fibroblasts and smooth muscle, this gene transcription is associated with the formation of a complex between the GR and another transcription factor, CCAAT enhancer-binding protein (C/EBP)-α. Airway smooth muscle cells from persons with asthma are deficient in C/EBP-α, which may explain the finding that CSs do not inhibit the proliferation of these cells in vitro. Whether this deficiency can explain the increased bulk of muscle in the asthmatic airway remains to be established. β2-Agonists can inhibit mast cell mediator release, but this response is susceptible to desensitization, a process that CSs can inhibit. CSs also can increase the transcription of the β2- receptor gene in the lung and the nasal mucosa. These effects of CSs mitigate against the reduced transcription of β2-receptors, which occurs as a consequence of long-term β2-agonist administration. Delineation of the exact mechanisms underlying these effects will ensure rational, direct therapy. © 2009 American College of Chest Physicians.	en_US
dc.relation.ispartof	Chest	en_US
dc.relation.isbasedon	10.1378/chest.09-0354	en_US
dc.subject.classification	Respiratory System	en_US
dc.subject.mesh	Muscle, Smooth	en_US
dc.subject.mesh	Respiratory System	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Asthma	en_US
dc.subject.mesh	Adrenal Cortex Hormones	en_US
dc.subject.mesh	Receptors, Adrenergic, beta	en_US
dc.subject.mesh	Adrenergic beta-Agonists	en_US
dc.subject.mesh	Delayed-Action Preparations	en_US
dc.subject.mesh	Drug Therapy, Combination	en_US
dc.subject.mesh	Administration, Inhalation	en_US
dc.title	Molecular mechanisms of combination therapy with inhaled corticosteroids and long-acting β-agonists	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	136	en_US
utslib.for	1103 Clinical Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	136	en_US

Abstract:

The treatment of asthma relies on the use of the following two major drug classes: β2-agonists, both short acting and long acting; and corticosteroids (CSs). Although the properties of each drug class are well described, their use in combination delivered either separately or through one device has provided some clear and important clinical advantages. The mechanisms underlying these interactions have emerged as novel and provocative. β2-Agonists can stimulate the glucocorticoid receptor (GR) and promote its translocation to the nucleus, resulting in increased CS-mediated gene transcription. In structural airway cells, such as fibroblasts and smooth muscle, this gene transcription is associated with the formation of a complex between the GR and another transcription factor, CCAAT enhancer-binding protein (C/EBP)-α. Airway smooth muscle cells from persons with asthma are deficient in C/EBP-α, which may explain the finding that CSs do not inhibit the proliferation of these cells in vitro. Whether this deficiency can explain the increased bulk of muscle in the asthmatic airway remains to be established. β2-Agonists can inhibit mast cell mediator release, but this response is susceptible to desensitization, a process that CSs can inhibit. CSs also can increase the transcription of the β2- receptor gene in the lung and the nasal mucosa. These effects of CSs mitigate against the reduced transcription of β2-receptors, which occurs as a consequence of long-term β2-agonist administration. Delineation of the exact mechanisms underlying these effects will ensure rational, direct therapy. © 2009 American College of Chest Physicians.

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